Galectin-3 in diabetic patients

Clin Chem Lab Med 2014; aop

Review

Giuseppe Pugliese * , Carla Iacobini , Carlo Ricci , Claudia Blasetti Fantauzzi

and Stefano Menini

Galectin-3 in diabetic patients

Abstract: Galectin-3 is a versatile molecule which exerts

several and sometimes opposite functions in various

pathophysiological processes. Recently, galectin-3 has

gained attention as a powerful predictor of heart fail-

ure and mortality, thus becoming a useful prognostic

marker in clinical practice. Moreover, though not spe-

cifically investigated in diabetic cohorts, plasma levels of

galectin-3 correlated with the prevalence of diabetes and

related metabolic conditions, thus suggesting that phar-

macological blockade of this lectin might be successful

for treating heart failure especially in subjects suffering

from these disorders. Indeed, galectin-3 is considered not

only as a marker of heart failure, but also as a mediator of

the disease, due to its pro-fibrotic action, though evidence

comes mainly from studies in galectin-3 deficient mice.

However, these studies have provided contrasting results,

with either attenuation or acceleration of organ fibrosis

and inflammation, depending on the experimental set-

ting and particularly on the levels of advanced glycation

endproducts (AGEs)/advanced lipoxidation endprod-

ucts (ALEs), of which galectin-3 is a scavenging receptor.

In fact, under conditions of increased AGE/ALE levels,

galectin-3 ablation was associated with tissue-specific

outcomes, reflecting the AGE/ALE-receptor function of

this lectin. Conversely, in experimental models of acute

inflammation and fibrosis, galectin-3 deficiency resulted

in attenuation of tissue injury. There is a need for prospec-

tive studies in diabetic patients specifically investigating

the relation of galectin-3 levels with complications and for

further animal studies in order to establish the effective

role of this lectin in organ damage before considering its

pharmacological blockade in the clinical setting.

Keywords: advanced glycation endproducts; advanced

lipoxidation endproducts; diabetes; fibrosis; galectin-3;

inflammation; receptor for advanced glycation endprod-

ucts (RAGE).

DOI 10.1515/cclm-2014-0187

Received February 20 , 2014 ; accepted May 26 , 2014

Introduction Galectin-3 is a member of an evolutionarily conserved

family of soluble β -galactoside-binding lectins. The struc-

ture of this 29- to 35-kDa protein consists of two domains,

the C-terminal carbohydrate recognition domain (CRD),

with highly conserved residues between members of the

family, and the N-terminal domain, with a unique short

end continuing into an intervening proline-glycine-ala-

nine-thyrosine-rich (PGAY) repeat motif [1] ( Figure 1 ).

Galectin-3 expression in tissues appears to be devel-

opmentally-regulated, being more abundant during

embryogenesis and development than in adult life, when

it is detected in various epithelial cells, cartilage and bone

as well as in inflammatory cells, either constitutively or in

a inducible fashion [2, 3] .

Galectin-3 shows a ubiquitous localization within

the cell and is also secreted into the extracellular space,

although it lacks a signal sequence for transfer into the

endoplasmic reticulum and Golgi compartments and entry

into classical secretory pathways [4] . This dual localiza-

tion of galectin-3 determines two different modes of inter-

action with proteins. Extracellular galectin-3 interacts

via the CRD [5] with the β -galactoside residues of several

extracellular matrix (ECM) and cell surface glycoproteins

[6] ; this is the classical lectin-glycoconjugate interaction.

Conversely, interactions of intracellular galectin-3 occur

via peptide-peptide associations mediated by its N-ter-

minus domain, though also the CRD may be involved at

this level [7] . These structural properties enable galectin-3

to bind several proteins, thus exerting multiple functions

*Corresponding author: Giuseppe Pugliese, MD, PhD, Department

of Clinical and Molecular Medicine, “ La Sapienza ” University,

Via di Grottarossa, 1035-1039, 00189 Rome, Italy,

Phone: + 39 0633775440, Fax: + 39-0633776327,

E-mail: [email protected]

Carla Iacobini, Carlo Ricci, Claudia Blasetti Fantauzzi and Stefano Menini: Department of Clinical and Molecular Medicine,

“ La Sapienza ” University, Rome, Italy

Brought to you by | Università degli Studi di GenovaAuthenticated | 130.251.200.3

Download Date | 6/25/14 10:32 AM

2 Pugliese et al.: Galectin-3 in diabetes

which make it a broad-spectrum biological response mod-

ifier involved in several disease conditions [8] (Figure 1).

Intracellularly, galectin-3 acts as a pre-mRNA splicing

factor [9] and regulates the cell cycle [10] by modulating

cell proliferation, death, and differentiation. Galectin-3

promotes cell proliferation [11, 12] and favors cell survival

by protecting from apoptosis induced by a variety of death

signals [12, 13] . By virtue of its pro-proliferative and anti-

apoptotic action, galectin-3 is considered as an imme-

diate early gene possibly implicated in tumor growth

[14] . However, galectin-3 can also be pro-apoptotic and

mediate T cell and neutrophil death [15] . Extracellularly,

galectin-3 regulates cell adhesion in a dual manner. Cell

surface galectin-3 promotes homo- and heterotypic cell-

to-cell interactions by serving as a cross-linking bridge

between adjacent cells [16, 17] , whereas it down-regulates

cell adhesion to the ECM component laminin via an asso-

ciation with the α 1 β 1-integrin receptor [18, 19] . This dual

function of galectin-3 on cell adhesion has made this

lectin an interesting target for the study of tumor progres-

sion and invasiveness [20] .

Another important function of (extracellular) galectin-3

is the modulation of immune/inflammatory function, with

both pro- and anti-inflammatory actions, depending on

multiple factors, such as type of inflammatory setting and

target cell/tissue [8] . Finally, galectin-3 facilitates repair of

tissue injury by promoting fibrogenesis [21] .

Recently, galectin-3 has gained attention as a power-

ful predictor of heart failure and mortality, thus becoming

a useful prognostic marker in clinical practice. Indeed,

galectin-3 is considered not only as a disease marker, but

also as a mediator of the development and progression

of heart failure [22] . In fact, since fibrosis is one of the

Lectin-glycoconjugateinteractions

C-terminaldomain

N-terminaldomain

Peptide-peptideassociations

Carbohydraterecognition

domain (~130 aa)

proline-glycine-alanine-tyrosine(PGAY) repeat motif (~100 aa)

Short end (~30 aa)

Figure 1 Galectin-3 structure and function.

aa, aminoacids; AGE, advanced glycation endproduct; ALE,

advanced lipoxidation endproduct.

main mechanisms underlying increased ventricular stiff-

ness and diastolic dysfunction [23] , the pro-fibrotic and

immune-modulatory properties of galectin-3 have been

claimed to explain the association between plasma levels

of this lectin and the presence and severity of heart failure

[24] . This interpretation is consistent with the finding that

galectin-3 was significantly correlated with serum markers

of cardiac ECM turnover in patients with heart failure [25] .

Moreover, though not specifically investigated in large

diabetic cohorts, plasma levels of galectin-3 correlated

with the prevalence of diabetes and the other diseases

conditions clustering in the metabolic syndrome [22] , thus

suggesting that pharmacological blockade of this lectin

might be successful for treating heart failure especially in

subjects with metabolic disorders.

However, studies in galectin-3 knockout animals

have provided contrasting results, with either attenua-

tion or acceleration of organ fibrosis and inflammation,

depending on the experimental setting and particularly

on the levels of advanced glycation endproducts (AGEs)/

advanced lipoxidation endproducts (ALEs), of which

galectin-3 is a scavenging receptor. In fact, under condi-

tions of increased AGE/ALE levels, galectin-3 ablation

was associated with tissue-specific outcomes, reflecting

the AGE/ALE-receptor function and possibly the direct

anti-inflammatory effects of this lectin [7] . Conversely, in

experimental models of acute inflammation and fibrosis,

deletion of Lgals3 gene resulted in prevention or attenua-

tion of target tissue injury [21] .

This article will briefly review the evidence supporting

the prognostic value of galectin-3 in clinical settings and

experimental data on the role of this lectin as a disease

mediator.

Galectin-3 as a marker of heart failure morbidity and mortality: human studies A large body of evidence from studies from both community-

based cohorts and selected populations has linked galec-

tin-3 plasma levels with presence and severity of heart

failure and all-cause and cardiovascular death.

Data from the general population come from 7968

subjects from the Prevention of Renal and Vascular ENd-

stage Disease (PREVEND) study and 3353 participants

in the Framingham Offspring Cohort. The first study

showed a strong relationship of galectin-3 plasma levels

with death, though only the association with all-cause



Pugliese et al.: Galectin-3 in diabetes 3

mortality remained significant after adjustment for tra-

ditional and non-traditional risk factors [26] . Likewise, in

the second survey, galectin-3 levels were independently

associated with an increased risk for incident heart failure

and all-cause mortality, even after adjustment for clinical

variables and brain natriuretic peptide (BNP) [27] .

Several studies have addressed the relation between

galectin-3 and heart failure in subjects suffering from

this disease condition, either acute or chronic, with

and without preserved left ventricular ejection fraction

(LVEF). In 599 patients presenting with dyspnea at the

emergency department, galectin-3 levels were signifi-

cantly higher in subjects with heart failure (209, 35%)

than in those without. Moreover, though inferior to levels

of amino-terminal pro-BNP (NT-proBNP) for diagnosis

of heart failure, elevated galectin-3 concentration was

the best independent predictor of mortality or the com-

bination of death/recurrent heart failure within 60 days.

Finally, Kaplan-Meier analyses showed that the combina-

tion of an elevated galectin-3 with NT-proBNP was a better

predictor of mortality than either of the two markers alone

[28] . In a nested case-control study among patients with

acute coronary syndrome from the Pravastatin or Atorv-

astatin Evaluation and Infection Therapy-Thrombolysis in

Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, baseline

galectin-3 levels showed a graded relationship with risk

of acute heart failure, which remained significant when

adjusted for hypertension, diabetes, and prior myocar-

dial infarction and heat failure, though it was attenuated

when BNP was added to the model [29] . In 592 subjects

with chronic heart failure from the Coordinating study

evaluating outcomes of Advising and Counseling in Heart

failure (COACH) trial, baseline galectin-3 levels were inde-

pendently associated with a composite of all-cause mor-

tality and hospitalization for heart failure. While serial

measurements of galectin-3 did not appear to add to the

prognostic power of single measurements, the predictive

value of plasma galectin-3 was stronger in heart failure

patients with preserved than in those with reduced LVEF

and increased when combined with BNP levels [30] . In the

Valsartan Heart Failure Trial (Val-HeFT), the increases in

galectin-3 over time, but not baseline levels, were inde-

pendently and significantly associated with risk of all-

cause mortality, first morbid event, and hospitalizations

for heart failure, even after adjusting for all the clinical

and biochemical baseline and serial change variables

including estimated glomerular filtration rate (eGFR)

and NT-proBNP [31] . Conversely, a combined analysis of

the Controlled Rosuvastatin Multinational Trial in Heart

Failure (CORONA) and COACH trial showed that increasing

galectin-3 levels over time, from a low to high galectin-3

category, were associated with significantly more heart

failure hospitalization and mortality compared with

stable or decreasing galectin-3 levels [32] .

At variance with the above reported studies, the asso-

ciation between galectin-3 levels and hospitalization-

free survival did not persist after adjustment for other

predictors, especially NT-proBNP, in the Heart Failure:

A Controlled Trial Investigating Outcomes of Exercise

TraiNing (HF-ACTION) [33] . Moreover, in older patients

with advanced chronic systolic heart failure of ischemic

etiology from the CORONA, elevated galectin-3 levels were

not associated with the composite outcome of cardiovas-

cular death, non-fatal myocardial infarction, or stroke

when adjusting for NT-proBNP [34] , though they predicted

response to statin therapy [35] . Finally, a recent retrospec-

tive analysis of 119 patients showed that galectin-3 levels

were similarly elevated in all patients with heart failure,

regardless of whether it was acute or chronic or systolic or

diastolic in nature. Moreover, galectin-3 levels in patients

with heart failure correlated with NT-proBNP, but this rela-

tionship was significantly attenuated after adjustment for

age and eGFR. Conversely, the relationship between galec-

tin-3 levels and eGFR persisted after corrections for age,

LVEF, and NT-proBNP and did not vary according to the

presence of heart failure [36] . These results suggest that the

prognostic role of galectin-3 in heart failure may be related

as much to renal impairment as to cardiac dysfunction

[37] . Indeed, a recent longitudinal analysis of 2450 partici-

pants in the Framingham Offspring Cohort showed that

elevated galectin-3 at baseline predicts a rapid decline in

eGFR and a higher risk of incident chronic kidney disease,

but not of incident albuminuria [38] , consistent with a pre-

vious study reporting an association of high plasma galec-

tin-3 levels with renal insufficiency and poorer survival in

patients with chronic systolic heart failure [39] .

In samples from the general population, circulating

galectin-3 levels correlated with age, female gender, and

markers of inflammation and target organ damage, but

also with prevalence of diabetes, obesity, hypertension,

and hypercholesterolemia and levels of components of the

metabolic syndrome [26, 27] . Moreover, galectin-3 levels

were found to be higher in subjects with obesity or type

2 diabetes [40] and a cross-sectional survey showed that

high galectin-3 values were associated with micro- and

macrovascular complications in diabetic patients [41] .

Thus, the higher galectin-3 levels in diabetic individuals

and in general in those with dysmetabolic disorders might

mark the increased susceptibility of these subjects toward

heart failure, though longitudinal studies of adequate

size and duration specifically testing this hypothesis are

needed.




Galectin-3 as a disease mediator: animal studies The human studies showed that galectin-3 is a powerful

predictor of the development and progression of heart

failure and suggested that this might be the case espe-

cially in high-risk individuals, such as subjects with

diabetes and other metabolic disorders. However, these

studies did not provide conclusive evidence that galec-

tin-3 plays a role of mediator in the setting of heart failure.

Thus, the concept that galectin-3 is causally implicated in

the development of this condition is still based on data

from experimental animal models showing that this lectin

is involved in organ fibrosis.

Several rodent models of pressure overload [42 – 44]

and aortic constriction [44] exhibited increased myocardial

and vascular expression of galectin-3. Moreover, infusion of

this lectin in pericardial sac of normal rats induced myocar-

dial fibrosis and left ventricular dysfunction [42, 45] , which

were prevented by the galectin-3 blocker N-acetyl-seryl-

aspartyl-lysyl-proline [45] . Other inhibitors of galectin-3,

modified citrus pectin and N-Lac, respectively, prevented

vascular fibrosis induced by aldosterone [43] and cardiac

remodeling occurring in both homozygous transgenic

TGRmRen2-27 (Ren-2) rats and mice subjected to transverse

aortic constriction [44] . Finally, galectin-3 deficient mice

were protected from the pro-fibrotic effects of aldosterone

treatment [43] and transverse aortic constriction [44] .

Galectin-3 ablation has been shown to result in atten-

uation of fibrosis also in other organs, such as the kidney,

lung and liver, when subjected to specific pro-fibrotic

stimuli. In fact, tubular atrophy and interstitial fibrosis

after renal transplantation [46] , renal tissue damage trig-

gered by ischemia and reperfusion injury [47] and renal

fibrosis induced by unilateral ureteric obstruction [48,

49] were attenuated by deletion of Lgals3 gene. Likewise,

in two well-characterized rodent models of lung fibrosis,

adeno-viral transforming growth factor (TGF)- β 1- and

bleomycin-induced, lesions were dramatically reduced in

mice deficient in galectin-3 [47, 50] . This was associated

with reduced TGF- β 1-induced epithelial to mesenchymal

transition (EMT) as well as myofibroblast activation and

collagen production, both in vivo and in vitro [46] . Similar

results were obtained in the bleomycin-induced lung

fibrosis model with an inhibitor of galectin-3, TD139 [47] .

Finally, galectin-3 disruption attenuated ECM production

both in vitro, in hepatic stellate cell cultures, and in vivo,

in the model of CCL 4 -induced cirrhosis, again through

blockade of TGF- β -mediated myofibroblast activation [51] .

Also liver fibrosis and cirrhosis induced by thioacetamide

were reversed by two galectin-3 inhibitors, GR-MD-02

(galactoarabino-rhamnogalaturonan) and GM-CT-01

(galactomannan) [52] .

Though the pro-fibrotic effect of galectin-3 is often

related to its pro-inflammatory action, this lectin was

shown to directly mediate transdifferentiation into colla-

gen-producing cells, thus leading to organ fibrosis. Maeda

et al. showed that galectin-3 induced hepatic stellate cells

transdifferentiation into myofibroblasts via the mitogen-

activated protein kinase/extracellular signal-regulated

kinase (ERK) – ERK 1/2 signaling pathway and, at variance

with galectin-1, in a protein kinase C- and A-dependent

manner [53] , whereas MacKinnon et al. showed that

galectin-3 ablation reduced alveolar epithelial cell EMT

in response to TGF- β 1 [50] . In addition, galectin-3 plays

a complex role in the modulation of immune/inflamma-

tory function, with distinct pro-inflammatory actions,

but also with relevant anti-inflammatory effects which

predominate under chronic conditions [7] . In acute set-

tings, galectin-3 favors the inflammatory response against

microbial infections. It is involved in the initiation phase

(chemoattraction of monocytes and macrophages, adhe-

sion of neutrophils to laminin and endothelial cells,

recognition of microbes) [54 – 56] , the induction of cel-

lular effector functions (respiratory burst in neutrophils

and monocytes with reactive oxygen species production,

phagocytosis) [57 – 60] , and the modulation of apoptotic

cell death [57, 61] . It also participates in allergic reaction

by inducing mediator release by mast cells [62] . Consist-

ently, studies in galectin-3 deficient mice with experimen-

tally-induced peritonitis have provided strong evidence of

its pro-inflammatory effects [63] . However, under chronic

conditions, galectin-3 appears to favor the resolution of

inflammation, thus limiting tissue injury and promoting

repair. In fact, it inhibits lipopolysaccharide-mediated

inflammation [64] , promotes T-cell apoptosis [65] and neg-

atively regulates TCR-mediated T-cell activation [66, 67] .

Moreover, MacKinnon et al. have shown that up-regula-

tion of galectin-3 expression is a feature of the alternative

macrophage (M2) phenotype and that release of galectin-3

by alternatively activated macrophages sustains the M2

phenotype contributing to some of its functions in vivo

[68] . For instance, Karlsson et al. showed that galectin-3,

by functioning as an opsonin, favors the phagocytic clear-

ance of apoptotic neutrophils by macrophages, a process

of crucial importance for termination of acute inflamma-

tion [69] . Accordingly, Caberoy et al. have recently dem-

onstrated that galectin-3 is a legitimate MerTK-specific

“ eat-me ” signal which stimulates phagocytosis of apo-

ptotic cells and cellular debris [70] . Finally, endothelial

galectin-3 might also play a role in chronic inflammatory




conditions, such as atherosclerosis and related cardio-

vascular events, since it was shown that its up-regulation

is part of the vascular response to diabetes [71] and that,

together with galectin-1, galectin-3 is a partner for von

Willebrand factor (VWF), participating in the modula-

tion of VWF-mediated thrombus formation [72] . Consist-

ently, the absence of galectin-1 and galectin-3 is associated

with more efficient formation of platelet-decorated VWF

strings along the endothelial surface and with enhanced

formation of arterial thrombi [72] .

In addition to exerting direct anti-inflammatory

effects, galectin-3 has also been shown to attenuate

inflammation by serving as a “ scavenger ” receptor for

AGEs and ALEs via induction of their internalization and

removal [73] , at variance with receptor for AGEs (RAGE),

which mediates the injurious effect of these byproducts

[74] . A galectin-3-deficient mouse model has been used to

investigate the role of this lectin in retinal, renal, vascular,

and liver tissue injury under various experimental condi-

tions of increased AGE/ALE levels, such as streptozotocin-

induced diabetes, normal aging, injection of the AGE/ALE

N ε -carboxymethyllysine (CML)-modified mouse serum

albumin, and feeding with a pro-atherogenic high fat diet

(HFD).

Lgals3 gene deletion effectively prevented early retinal

changes associated with streptozotocin-induced diabetes

[75] , whereas it abolished the AGE-mediated increase in

retinal ischemia and restored the neovascular response to

that seen in controls [76] .

Galectin-3 ablation resulted in accelerated diabetes-

induced glomerulopathy, as shown by the more marked

glomerular lesions and the significantly higher increase

in albuminuria and mesangial expansion, the func-

tional and structural hallmarks of glomerulopathy [77] .

Moreover, both circulating and renal tissue levels of AGEs

increased more markedly in response to diabetes and

renal cortex RAGE expression was up-regulated even in

control animals and increased in a significantly higher

extent in diabetic mice. Similar features of more marked

fibrosis and inflammation were observed in the aging [78] ,

AGE-injection [79] , and HFD [80] models.

Likewise, galectin-3 deficient animals showed accel-

erated atherosclerosis when fed a HFD, with a higher

lesion area and length and particularly with develop-

ment of complex lesions, as compared with the simple

fatty streaks observed in the wild-type mice. This was

also associated with increased aortic levels of the AGEs/

ALEs CML and protein adducts of 4-hydroxy-2-nonenal

and expression of RAGE, and with unique inflammatory

features with a more marked infiltration of monocytes/

macrophages and, particularly, with the presence of an

extensive infiltrate of T lymphocytes with predominant

Th-1 phenotype, as shown by CD3 and CXCR3 staining [81] .

In contrast to these findings, two independent studies con-

ducted in ApoE-null mice, a mouse model of atherosclero-

sis, have suggested a pathogenic role of galectin-3. In the

first study, Nachtigal et al. showed that ApoE null mice on

a standard chow develop attenuated atherosclerosis when

crossbred with galectin-3 deficient mice [82] . A possible

explanation for this difference is that, at variance with the

study of Iacobini et al. [81] , while the wild-type mice were

on a C57BL/6J background, the galectin-3 deficient mice

were on a mixed background between C57BL/6J and 129/

SvEv, a strain which has long been recognized to be less

prone to develop atherosclerotic lesions than the C57BL/6J

[83, 84] . In the second study, MacKinnon et al. have also

reported that galectin-3 ablation decreases atherosclero-

sis in ApoE-null mice fed a high-cholesterol Western diet

[85] . However, in contrast with the reduced atherosclerotic

burden, and consistently with data obtained by Iacobini

et al., galectin-3 ablation induced a less stable plaque

phenotype, characterized by reduced M2 macrophages

polarization and decreased collagen content [85] . A final

consideration about these apparently conflicting findings

is that results in double knockout mice could be related

to yet unknown specific interactions between the two

genotypes.

In contrast with findings in the kidney and the aorta,

where galectin-3 ablation was associated with an exac-

erbation of the disease [77 – 81] , in the liver of the same

animals, HFD-induced non-alcoholic steatohepatitis

(NASH) was attenuated by galectin-3 ablation, as indi-

cated by the lower extent of inflammation and fibrosis,

the two hallmarks of NASH. Consistently, liver AGE and

ALE levels and RAGE expression were decreased in galec-

tin-3 deficient mice as opposed to wild-type. Moreover,

galectin-3 silencing reduced the uptake of the AGE CML

by liver sinusoidal endothelial cells, the main site of AGE

removal, thus indicating that this lectin [86] , at variance

with scavenger receptor A and CD36 [87, 88] , is a major

scavenger receptor in the liver. Therefore, in galectin-3

deficient mice, the reduced hepatic uptake of AGEs/ALES

could have played a role both in the prevention of NASH

and the increase of circulating levels of these byproducts.

These studies demonstrated that lesions were accelerated

in tissues where galectin-3 ablation was associated with

increased tissue AGE/ALE deposition and consequent

RAGE overexpression (i.e., in the kidney and aorta) and

attenuated where the absence of this lectin resulted in

reduced ALE/ALE accumulation, with lack of stimulation

of RAGE expression (i.e., in the liver). This prompted the

hypothesis that galectin-3 plays a supportive role in the




pathogenesis of complications of metabolic disorders,

i.e., a role which is exerted through a dual, tissue-specific

modulation of RAGE expression, depending on the ana-

bolic or catabolic role of the tissue in the metabolism of

AGEs/ALEs. This view is supported by the observations

that diabetic glomerulopathy was accelerated in trans-

genic mice over-expressing RAGE [89] ; diabetes-induced

atherogenesis was attenuated in ApoE null mice by

RAGE blockade with soluble RAGE [90] ; and liver fibro-

sis induced by administration of carbon tetrachloride

to normal rats was ameliorated by RAGE silencing [91] .

However, some AGE/ALE- and RAGE-independent effects

of galectin-3 might also be claimed to explain these find-

ings, especially the direct anti-inflammatory effect of this

lectin at the aortic level, and the pro-fibrotic action at the

hepatic level ( Figure 2 ). In particular, the distinct inflam-

matory features of galectin-3 deficient animals at the

aortic and renal level may be explained also by the lack of

direct anti-inflammatory actions of this lectin. Likewise,

the lack of the pro-fibrotic effect of galectin-3 may have

participated in the attenuation of NASH and, together

with the impaired clearance of apoptotic cells favored

by the deficiency of this lectin, to the enlargement of the

necrotic core and thinning of the fibrous cap in plaques.

Finally, recent evidence suggests that galectin-3 might

be also involved in the regulation of glucose homeo-

stasis by acting at the level of adipose tissue and pan-

creatic islets, thus participating in the pathogenesis of

obesity and type 2 diabetes. Two independent research

Vessels Kidney

Liver

ROS

RO

S

AGE/ALE production

AGE/ALE accumulation

Overload ofdetoxification system

AGE/ALE contentCirculatingAGEs/ALEs

AGE/ALE disposal byresident cells and macrophages

AGE/ALE uptakeby LSECs and KCs

Deletion of Lgals3 gene

Hyperglycemia Hyperlipidemia

NASH

RAGE

RAGE

Atherogenesis Renal disease

Figure 2 Galectin-3 ablation and renal, vascular and liver disease

in metabolic disorders.

AGE, advanced glycation endproducts; ALE, advanced lipoxidation

endproducts; LSECs, liver sinusoidal endothelial cells; KCs, Kupffer

cells; NASH, non-alcoholic steatohepatitis; RAGE, receptor for AGEs;

ROS, reactive oxygen species.

laboratories investigated the role of galectin-3 in the mod-

ulation of metabolic disorders induced by an obesogenic

HFD containing 60% calories from saturated fat [92, 93] .

Both studies demonstrated a protective role of galectin-3

toward obesity and type 2 diabetes, via modulation of the

responsiveness of innate and adaptive immunity to over-

nutrition [92, 93] . Also in both studies, increased adiposity

and inflammation at the visceral adipose tissue (VAT) and

systemic level were associated with altered glucose home-

ostasis, as evidenced by increased fasting glucose and gly-

cated hemoglobin levels [92, 93] . Moreover, Pejnovic et al.

[92] showed that, in galectin-3 deficient mice fed a HFD,

impaired glucose metabolism was associated with a more

marked insulin resistance, as assessed by the HOMA-IR,

at variance with findings from Pang et al. [93] . In addi-

tion to VAT, Pejnovic et al. found increased inflammation

also in pancreatic islets from galectin-3 deficient mice fed

a HFD, as demonstrated by a marked infiltration of cells

of the macrophage/dendritic lineage with various degrees

of insulitis [92] . These authors also showed that galectin-3

deficient mice fed a HFD had increased accumulation of

AGEs in the islets [92] , a finding in keeping with the AGE-

receptor function of galectin-3, which favors AGE degrada-

tion [7] . These data indicate an important role of galectin-3

in protecting islets from inflammation and injury induced

by a variety of stimuli associated with overfeeding, includ-

ing AGEs. This view is also consistent with the finding that

the circulating levels of galectin-3 observed in patients

with type 2 diabetes correlate positively with body mass

index and negatively with glycated hemoglobin [40] .

Conclusions

Existing literature indicates that galectin-3 is a versatile

molecule serving as a broad-spectrum biological response

modifier. As a consequence, it exerts numerous and some-

times opposite functions.

On the grounds of human studies addressing the role

of galectin-3 as a marker of morbidity and mortality for

heart failure, this lectin should be considered as a “ bad-

guy ” and, hence, amenable of pharmacological blockade.

However, studies conducted in vitro and in experimental

animal models of diabetes have indicated that it might be a

“ good-guy ” by virtue of its participation in the endothelial

response to diabetes, regulation of thrombus formation,

and modulation of the immune/inflammatory system. In

general, factors involved in determining the final outcome

favored by galectin-3 are the type of injurious stimulus,

the context of organ damage, and the cellular localization




of this lectin. In particular, in diabetic subjects, galectin-3

plays different roles, either dependent on or independ-

ent from its AGE/ALE binding function. Moreover, ALE/

AGE-dependent effects of galectin-3 vary among different

organs, reflecting tissue differences in the function of the

ALE/AGE receptor system, which, in the liver, is mainly

implicated in ALE/AGE removal from circulation and

detoxification. Therefore, although most of the studies

agree in considering galectin-3 as a marker of inflamma-

tion and fibrosis, studies on experimental animal models

of metabolic disorders suggest that the increased expres-

sion of galectin-3 may be part of an adaptive response to

tissue injury, favoring resolution of inflammation and

opposing to chronification of the inflammatory process.

Consistently, galectin-3 ablation induces a pro-inflamma-

tory phenotype characterized by an increased systemic,

pancreatic and VAT inflammatory response to metabolic

stimuli and an exacerbated vascular and renal tissue

damage induced by diabetes and related disorders.

Based on these considerations, there is the need of

large, prospective studies specifically investigating the

relation of plasma levels of galectin-3 with long-term com-

plications in diabetic patients. However, prior to inves-

tigating the effect of selective inhibitors of circulating

galectin-3 in diabetic and non-diabetic patients, further

research on animal models is required in order to estab-

lish whether this lectin is a mediator of organ damage, a

simple bystander, or a protective agent in these chronic

conditions and, hence, whether or not it is amenable of

pharmacological blockade.

Acknowledgments: The authors ’ work reviewed in

this paper was supported by grants from the European

Foundation for the Study of Diabetes/Juvenile Diabetes

Research Foundation/Novo Nordisk, the Telethon Foun-

dation, the Ministry of Health of Italy, the Ministry of Edu-

cation, University and Research of Italy, and the Diabetes,

Endocrinology and Metabolism Foundation.

Conflict of interest statement

Authors ’ conflict of interest disclosure: The authors

stated that there are no conflicts of interest regarding the

publication of this article. Research support played no

role in the study design; in the collection, analysis, and

interpretation of data; in the writing of the report; or in the

decision to submit the report for publication.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

References 1. Barondes SH, Cooper DN, Gitt MA, Leffler H. Galectins. Structure

and function of a large family of animal lectins. J Biol Chem

1994;269:20807 – 10.

2. Aubin JE, Liu F, Malaval L, Gupta AK. Osteoblast and chondro-

blast differentiation. Bone 1995;17(Suppl):77S – 83S.

3. Liu FT. Galectins: novel anti-inflammatory drug targets. Expert

Opin Ther Targets 2002;6:461 – 8.

4. Menon RP, Hughes RC. Determinants in the N-terminal domains

of galectin-3 for secretion by a novel pathway circumvent-

ing the endoplasmic reticulum-Golgi complex. Eur J Biochem

1999;264:569 – 76.

5. Funasaka T, Balan V, Raz A, Wong RW. Nucleoporin Nup98

mediates galectin-3 nuclear-cytoplasmic trafficking. Biochem

Biophys Res Commun 2013;434:155 – 61.

6. Vijayakumar S, Peng H, Schwartz GJ. Galectin-3 mediates

oligomerization of secreted hensin using its carbohydrate-rec-

ognition domain. Am J Physiol Renal Physiol 2013;305:F90 – 9.

7. Iacobini C, Amadio L, Oddi G, Ricci C, Barsotti P, Missori S, et al.

Role of galectin-3 in diabetic nephropathy. J Am Soc Nephrol

2003;14(Suppl):S264 – 70.

8. Dumic J, Dabelic S, Fl ö gel M. Galectin-3: an open-ended story.

Biochim Biophys Acta 2006;1760:616 – 35.

9. Dagher SF, Wang JL, Patterson RJ. Identification of galectin-3

as a factor in pre-mRNA splicing. Proc Natl Acad Sci USA

1995;92:1213 – 7.

10. Kim HR, Lin HM, Biliran H, Raz A. Cell cycle arrest and inhibition

of anoikis by galectin-3 in human breast epithelial cells. Cancer

Res 1999;59:4148 – 54.

11. Inohara H, Akahani S, Raz A. Galectin-3 stimulates cell prolifera-

tion. Exp Cell Res 1998;245:294 – 302.

12. Yang RY, Hsu DK, Liu F-T. Expression of galectin-3 modu-

lates T-cell growth and apoptosis. Proc Natl Acad Sci USA

1996;93:6737 – 42.

13. Akahani S, Nangia-Makker P, Inohara H, Kim HR, Raz A.

Galectin-3: a novel antiapoptotic molecule with a functional

BH1 (NWGR) domain of Bcl-2 family. Cancer Res 1997;57:

5272 – 6.

14. Liu FT, Rabinovich GA. Galectins as modulators of tumour pro-

gression. Nat Rev Cancer 2005;5:29 – 41.

15. Yang R, Rabinovich G, Liu F. Galectins: structure, function and

therapeutic potential. Expert Rev Mol Med 2008;10:1 – 24.

16. Inohara H, Raz A. Functional evidence that cell surface

galectin-3 mediates homotypic cell adhesion. Cancer Res

1995;55:3267 – 71.

17. Friedrichs J, Torkko JM, Helenius J, Ter ä v ä inen TP, F ü llekrug J,

Muller DJ, et al. Contributions of galectin-3 and -9 to epithelial

cell adhesion analyzed by single cell force spectroscopy. J Biol

Chem 2007;282:29375 – 83.

18. Ochieng J, Leite-Browning ML, Warfield P. Regulation of cellular

adhesion to extracellular matrix proteins by galectin-3. Biochem


19. Friedrichs J, Manninen A, Muller DJ, Helenius J. Galectin-3 regu-

lates integrin alpha2beta1-mediated adhesion to collagen-I and

-IV. J Biol Chem 2008;283:32264 – 72.

20. Hughes RC. Galectins as modulators of cell adhesion. Biochimie

2001;83:667 – 76.

21. Henderson NC, Sethi T. The regulation of inflammation by galec-

tin-3. Immunol Rev 2009;230:160 – 71.




22. de Boer RA, Edelmann F, Cohen-Solal A, Mamas MA, Maisel A,

Pieske B. Galectin-3 in heart failure with preserved ejection frac-

tion. Eur J Heart Fail 2013;15:1095 – 101.

23. Martos R, Baugh J, Ledwidge M, O ’ Loughlin C, Conlon C, Patle A,

et al. Diastolic heart failure: evidence of increased myocardial

collagen turnover linked to diastolic dysfunction. Circulation

2007;115:888 – 95.

24. de Boer RA, Voors AA, Muntendam P, van Gilst WH, van Veldhu-

isen DJ. Galectin-3: a novel mediator of heart failure develop-

ment and progression. Eur J Heart Fail 2009;11:811 – 7.

25. Lin YH, Lin LY, Wu YW, Chien KL, Lee CM, Hsu RB, et al. The

relationship between serum galectin-3 and serum markers of

cardiac extracellular matrix turnover in heart failure patients.

Clin Chim Acta 2009;409:96 – 9.

26. de Boer RA, van Veldhuisen DJ, Gansevoort RT, Muller Kobold

AC, van Gilst WH, Hillege HL, et al. The fibrosis marker galec-

tin-3 and outcome in the general population. J Intern Med

2012;272:55 – 64.

27. Ho JE, Liu C, Lyass A, Courchesne P, Pencina MJ, Vasan RS, et al.

Galectin-3, a marker of cardiac fibrosis, predicts incident heart

failure in the community. J Am Coll Cardiol 2012;60:1249 – 56.

28. van Kimmenade RR, Januzzi JL Jr, Ellinor PT, Sharma UC, Bakker

JA, Low AF, et al. Utility of amino-terminal pro-brain natriuretic

peptide, galectin-3, and apelin for the evaluation of patients

with acute heart failure. J Am Coll Cardiol 2006;48:1217 – 24.

29. Grandin EW, Jarolim P, Murphy SA, Ritterova L, Cannon CP,

Braunwald E, et al. Galectin-3 and the development of heart fail-

ure after acute coronary syndrome: pilot experience from PROVE

IT-TIMI 22. Clin Chem 2012;58:267 – 73.

30. de Boer RA, Lok JA, Jaarsma T, van der Meer P, Voors AA,

Hillege HL, et al. Predictive value of plasma galectin-3 levels in

heart failure with reduced and preserved ejection fraction. Ann

Med 2011;43:60 – 8.

31. Anand IS, Rector TS, Kuskowski M, Adourian A, Muntendam P,

Cohn JN. Baseline and serial measurements of galectin-3 in

patients with heart failure: relationship to prognosis and effect

of treatment with valsartan in the Val-HeFT. Eur J Heart Fail

2013;15:511 – 8.

32. van der Velde AR, Gullestad L, Ueland T, Aukrust P, Guo Y, Adou-

rian A, et al. Prognostic value of changes in galectin-3 levels

over time in patients with heart failure: data from CORONA and

COACH. Circ Heart Fail 2013;6:219 – 26.

33. Felker GM, Fiuzat M, Shaw LK, Clare R, Whellan DJ, Bettari L,

et al. Galectin-3 in ambulatory patients with heart failure:

results from the HF-ACTION study. Circ Heart Fail 2012;5:72 – 8.

34. Gullestad L, Ueland T, Kjekshus J, Nymo SH, Hulthe J, Muntendam P,

et al. The predictive value of galectin-3 for mortality and cardiovas-

cular events in the Controlled Rosuvastatin Multinational Trial in

Heart Failure (CORONA). Am Heart J 2012;164:878 – 83.

35. Gullestad L, Ueland T, Kjekshus J, Nymo SH, Hulthe J, Munten-

dam P, et al; CORONA Study Group. Galectin-3 predicts response

to statin therapy in the Controlled Rosuvastatin Multinational

Trial in Heart Failure (CORONA). Eur Heart J 2012;33:2290 – 6.

36. Gopal DM, Kommineni M, Ayalon N, Koelbl C, Ayalon R, Biolo

A, et al. Relationship of plasma galectin-3 to renal function in

patients with heart failure: effects of clinical status, pathophysi-

ology of heart failure, and presence or absence of heart failure.

J Am Heart Assoc 2012;1:e000760.

37. Ahmad T, Felker GM. Galectin-3 in heart failure: more answers or

more questions ? J Am Heart Assoc 2012;1:e004374.

38. O ’ Seaghdha CM, Hwang SJ, Ho JE, Vasan RS, Levy D, Fox CS.

Elevated galectin-3 precedes the development of CKD. J Am Soc

Nephrol 2013;24:1470 – 7.

39. Tang WH, Shrestha K, Shao Z, Borowski AG, Troughton RW,

Thomas JD, et al. Usefulness of plasma galectin-3 levels in

systolic heart failure to predict renal insufficiency and survival.

Am J Cardiol 2011;108:385 – 90.

40. Weigert J, Neumeier M, Wanninger J, Bauer S, Farkas S,

Scherer MN, et al. Serum galectin-3 is elevated in obesity and

negatively correlates with glycosylated hemoglobin in type 2

diabetes. J Clin Endocrinol Metab 2010;95:1404 – 11.

41. Jin QH, Lou YF, Li TL, Chen HH, Liu Q, He XJ. Serum galectin-3:

a risk factor for vascular complications in type 2 diabetes mel-

litus. Chin Med J 2013;126:2109 – 15.

42. Sharma UC, Pokharel S, van Brakel TJ, van Berlo JH, Cleutjens JP,

Schroen B, et al. Galectin-3 marks activated macrophages in

failure-prone hypertrophied hearts and contributes to cardiac

dysfunction. Circulation 2004;110:3121 – 8.

43. Calvier L, Miana M, Reboul P, Cachofeiro V, Martinez-Martinez E,

de Boer RA, et al. Galectin-3 mediates aldosterone-induced

vascular fibrosis. Arterioscler Thromb Vasc Biol 2013;33:67 – 75.

44. Yu L, Ruifrok WP, Meissner M, Bos EM, van Goor H, Sanjabi

B, et al. Genetic and pharmacological inhibition of galectin-3

prevents cardiac remodeling by interfering with myocardial

fibrogenesis. Circ Heart Fail 2013;6:107 – 17.

45. Liu YH, D ’ Ambrosio M, Liao TD, Peng H, Rhaleb NE, Sharma U,

et al. N-Acetyl-seryl-aspartyl-lysyl-proline prevents cardiac

remodelling and dysfunction induced by galectin-3, a mamma-

lian adhesion/growth-regulatory lectin. Am J Physiol Heart Circ

Physiol 2009;296:H404 – 12.

46. Dang Z, MacKinnon A, Marson LP, Sethi T. Tubular atrophy and

interstitial fibrosis after renal transplantation is dependent on

galectin-3. Transplantation 2012;93:477 – 84.

47. Fernandes Bertocchi AP, Campanhole G, Wang PH, Gon ç alves

GM, Dami ã o MJ, Cenedeze MA, et al. A Role for galectin-3 in

renal tissue damage triggered by ischemia and reperfusion

injury. Transpl Int 2008;21:999 – 1007.

48. Henderson NC, Mackinnon AC, Farnworth SL, Kipari T, Haslett C,

Iredale JP, et al. Galectin-3 expression and secretion links

macrophages to the promotion of renal fibrosis. Am J Pathol

2008;172:288 – 98.

49. Okamura DM, Pasichnyk K, Lopez-Guisa JM, Collins S, Hsu DK,

Liu FT, et al. Galectin-3 preserves renal tubules and modulates

extracellular matrix remodeling in progressive fibrosis. Am J

Physiol Renal Physiol 2011;300:F245 – 53.

50. MacKinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ,

Delaine T, et al. Regulation of transforming growth factor-

β 1 – driven lung fibrosis by galectin-3. Am J Respir Crit Care Med

2012;185:537 – 46.

51. Henderson NC, Mackinnon AC, Farnworth SL, Poirier F, Russo FP,

Iredale JP, et al. Galectin-3 regulates myofibroblast activation

and hepatic fibrosis. Proc Natl Acad Sci USA 2006;103:5060 – 5.

52. Traber PG, Chou H, Zomer E, Hong F, Klyosov A, Fiel MI, et al.

Regression of fibrosis and reversal of cirrhosis in rats by galec-

tin inhibitors in thioacetamide-induced liver disease. PLoS One

2013;8:e75361.

53. Maeda N, Kawada N, Seki S, Arakawa T, Ikeda K, Iwao H, et al.

Stimulation of proliferation of rat hepatic stellate cells by galec-

tin-1 and galectin-3 through different intracellular signaling

pathways. J Biol Chem 2003;278:18938 – 44.




54. Sano H, Hsu DK, Yu L, Apgar JR, Kuwabara I, Yamanaka T, et al.

Human galectin-3 is a novel chemoattractant for monocytes and

macrophages. J Immunol 2000;165:2156 – 64.

55. John CM, Jarvis GA, Swanson KV, Leffler H, Cooper MD,

Huflejt ME, et al. Galectin-3 binds lactosaminylated lipooli-

gosaccharides from Neisseria gonorrhoeae and is selectively

expressed by mucosal epithelial cells that are infected. Cell

Microbiol 2002;4:649 – 62.

56. Mey A, Leffler H, Hmama Z, Normier G, Revillard JP. The animal

lectin galectin-3 interacts with bacterial lipopolysaccharides via

two independent sites. J Immunol 1996;156:1572 – 7.

57. Farnworth SL, Henderson NC, Mackinnon AC, Atkinson KM,

Wilkinson T, Dhaliwal K, et al. Galectin-3 reduces the severity of

pneumococcal pneumonia by augmenting neutrophil function.

Am J Pathol 2008;172:395 – 405.

58. Karlsson A, Follin P, Leffler H, Dahlgren C. Galectin-3 activates

the NADPH-oxidase in exudated but not peripheral blood neutro-

phils. Blood 1998;91:3430 – 8.

59. Yamaoka A, Kuwabara I, Frigeri LG, Liu FT. A human lectin, galec-

tin-3 (epsilon bp/Mac-2), stimulates superoxide production by

neutrophils. J Immunol 1995;154:3479 – 87.

60. Sano H, Hsu DK, Apgar JR, Yu L, Sharma BB, Kuwabara I, et al.

Critical role of galectin-3 in phagocytosis by macrophages. J Clin

Invest 2003;112:389 – 97.

61. Hsu DK, Liu FT. Regulation of cellular homeostasis by galectins.

Glycoconj J 2004;19:507 – 15.

62. Frigeri LG, Zuberi RI, Liu FT. Epsilon BP, a beta-galactoside-bind-

ing animal lectin, recognizes IgE receptor (Fc epsilon RI) and

activates mast cells. Biochemistry 1993;32:7644 – 9.

63. Hsu DK, Yang RY, Pan Z, Yu L, Salomon DR, Fung-Leung WP,

et al. Targeted disruption of the galectin-3 gene results in

attenuated peritoneal inflammatory responses. Am J Pathol

2000;156:1073 – 83.

64. Li Y, Komai-Koma M, Gilchrist DS, Hsu DK, Liu FT, Springall T,

et al. Galectin-3 is a negative regulator of lipopolysaccharide-

mediated inflammation. J Immunol 2008;181:2781 – 9.

65. Fukumori T, Takenaka Y, Yoshii T, Kim HR, Hogan V, Inohara H,

et al. CD29 and CD7 mediate galectin-3-induced type II T-cell

apoptosis. Cancer Res 2003;63:8302 – 11.

66. Demetriou M, Granovsky M, Quaggin S, Dennis JW. Negative

regulation of T-cell activation and autoimmunity by Mgat5

N-glycosylation. Nature 2001;409:733 – 9.

67. Chen HY, Fermin A, Vardhana S, Weng IC, Lo KF, Chang EY,

et al. Galectin-3 negatively regulates TCR-mediated CD4 + T-cell

activation at the immunological synapse. Proc Natl Acad Sci USA

2009;106:14496 – 501.

68. MacKinnon AC, Farnworth SL, Hodkinson PS, Henderson NC,

Atkinson KM, Leffler H, et al. Regulation of alternative mac-

rophage activation by galectin-3. J Immunol 2008;180:2650 – 8.

69. Karlsson A, Christenson K, Matlak M, Bj ö rstad A, Brown KL,

Telemo E, et al. Galectin-3 functions as an opsonin and

enhances the macrophage clearance of apoptotic neutrophils.

Glycobiology 2009;19:16 – 20.

70. Caberoy NB, Alvarado G, Bigcas JL, Li W. Galectin-3 is a new

MerTK-specific eat-me signal. J Cell Physiol 2012;227:401 – 7.

71. Darrow AL, Shohet RV, Maresh JG. Transcriptional analysis of the

endothelial response to diabetes reveals a role for galectin-3.

Physiol Genomics 2011;43:1144 – 52.

72. Saint-Lu N, Oortwijn BD, Pegon JN, Odouard S, Christophe OD,

de Groot PG, et al. Identification of galectin-1 and galectin-3 as

novel partners for von Willebrand factor. Arterioscler Thromb

Vasc Biol 2012;32:894 – 901.

73. Zhu W, Sano H, Nagai R, Fukuhara K, Miyazaki A, Horiuchi S.

The role of galectin-3 in endocytosis of advanced glycation

end products and modified low density lipoproteins. Biochem


74. Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor

RAGE as a progression factor amplifying immune and inflamma-

tory responses. J Clin Invest 2001;108:949 – 55.

75. Canning P, Glenn JV, Hsu DK, Liu F-T, Gardiner TA, Stitt AW. Inhi-

bition of advanced glycation and absence of galectin-3 prevent

blood-retinal barrier dysfunction during short-term diabetes.

Exp Diabetes Res 2007;2007:51837.

76. Stitt AW, McGoldrick C, Rice-McCaldin A, McCance DR, Glenn JV,

Hsu DK, et al. Impaired retinal angiogenesis in diabetes: role

of advanced glycation end products and galectin-3. Diabetes

2005;54:785 – 94.

77. Pugliese G, Pricci F, Iacobini C, Leto G, Amadio L, Barsotti P,

et al. Accelerated diabetic glomerulopathy in galectin-3/AGE-

receptor-3 knockout mice. FASEB J 2001;15:2471 – 9.

78. Iacobini C, Oddi G, Menini S, Amadio L, Ricci C, Barsotti P, et al.

Development of age-dependent glomerular lesions in galec-

tin-3/AGE-receptor-3 knockout and wild type mice. Am J Physiol

Renal Physiol 2005;289:F611 – 21.

79. Iacobini C, Menini S, Oddi G, Ricci C, Amadio L, Pricci F, et al.

Galectin-3/AGE-receptor 3 knockout mice show accelerated

AGE-induced glomerular injury. Evidence for a protective role of

galectin-3 as an AGE-receptor. FASEB J 2004;18:1773 – 5.

80. Iacobini C, Menini S, Ricci C, Scipioni A, Sansoni V, Mazzitelli G,

et al. Advanced lipoxidation end-products mediate lipid-induced

glomerular injury: role of receptor-mediated mechanisms.

J Pathol 2009;218:360 – 9.

81. Iacobini C, Menini S, Ricci C, Scipioni A, Sansoni V, Cordone S,

et al. Accelerated lipid-induced atherogenesis in galectin-

3-deficient mice: role of lipoxidation via receptor-mediated

mechanisms. Arterioscler Thromb Vasc Biol 2009;29:831 – 6.

82. Nachtigal M, Ghaffar A, Mayer EP. Galectin-3 gene inactivation

reduces atherosclerotic lesions and adventitial inflammation in

ApoE-deficient mice. Am J Pathol 2008;172:247 – 55.

83. Paigen B, Morrow A, Brandon C, Mitchell D, Holmes P. Variation

in susceptibility to atherosclerosis among inbred strains of

mice. Atherosclerosis 1985;57:65 – 73.

84. Maeda N, Johnson L, Kim S, Hagaman J, Friedman M, Reddick R.

Anatomical differences and atherosclerosis in apolipoprotein

E-deficient mice with 129/SvEv and C57BL/6 genetic back-

grounds. Atherosclerosis 2007;195:75 – 82.

85. MacKinnon AC, Liu X, Hadoke PW, Miller MR, Newby DE, Sethi T.

Inhibition of galectin-3 reduces atherosclerosis in apolipopro-

tein E-deficient mice. Glycobiology 2013;23:654 – 63.

86. Iacobini C, Menini S, Ricci C, Blasetti Fantauzzi C, Scipioni A,

Salvi L, et al. Galectin-3 ablation protects mice from diet-

induced nonalcoholic steatohepatitis. Major scavenging role of

galectin-3 in liver. J Hepatol 2011;54:975 – 83.

87. Matsumoto K, Sano H, Nagai R, Suzuki H, Kodama T, Yoshida M,

et al. Endocytic uptake of advanced glycation end products by

mouse liver sinusoidal cells is mediated by a scavenger recep-

tor distinct from the macrophage scavenger receptor class A.

Biochem J 2000;352:233 – 40.

88. Nakajou K, Horiuchi S, Sakai M, Hirata K, Tanaka M, Takeya M,

et al. CD36 is not involved in scavenger receptor-mediated




endocytic uptake of glycolaldehyde- and methylglyoxal-

modified proteins by liver endothelial cells. J Biochem

2005;137:607 – 16.

89. Yamamoto Y, Kato I, Doi T, Yonekura H, Ohashi S, Takeuchi M,

et al. Development and prevention of advanced diabetic

nephropathy in RAGE-overexpressing mice. J Clin Invest

2001;108:261 – 8.

90. Park L, Raman KG, Lee KJ, Lu Y, Ferran LJ Jr, Chow WS, et al.

Suppression of accelerated diabetic atherosclerosis by the

soluble receptor for advanced glycation endproducts. Nat Med

1998;4:1025 – 31.

91. Xia JR, Liu NF, Zhu NX. Specific siRNA targeting the receptor for

advanced glycation end products inhibits experimental hepatic

fibrosis in rats. Int J Mol Sci 2008;9:638 – 61.

92. Pejnovic NN, Pantic JM, Jovanovic IP, Radosavljevic GD,

Milovanovic MZ, Nikolic IG, et al. Galectin-3 deficiency acceler-

ates high-fat diet-induced obesity and amplifies inflammation in

adipose tissue and pancreatic islets. Diabetes 2013;62:1932 – 44.

93. Pang J, Rhodes DH, Pini M, Akasheh RT, Castellanos KJ,

Cabay RJ, et al. Increased adiposity, dysregulated glucose

metabolism and systemic inflammation in Galectin-3 KO mice.

PLoS One 2013;8:e57915.

Giuseppe Pugliese, MD, PhD, was born in Rome on 29 November,

1954. His professional education includes: degree in Medicine

(1978, cum laude), Specialty Board Certification in Internal Medicine

(1983, cum laude) and Endocrinology and Metabolism (1992, cum

laude), PhD in Endocrinology and Metabolism (1990), all at La Sapi-

enza University of Rome, and Research Fellow/Associate at Wash-

ington University, St. Louis, MO, USA (1986 – 1988). Currently, he is

an Associate Professor at the Department of Clinical and Molecular

Medicine, La Sapienza University of Rome (since 2000) and Chief of

the Diabetes Unit of Sant ’ Andrea Hospital in Rome (since 2010). His

research fields include the molecular mechanisms of diabetic com-

plications, the natural history of diabetic nephropathy, and the role

of physical activity/exercise in diabetic patients. He is author of 109

papers published in peer-reviewed journals and has been recipi-

ent of several prizes, including the Golgi Prize from the European

Association for the Study of Diabetes.

Carla Iacobini, PhD, was born in Rome on 17 July, 1962. She received

her MSc in Biology in 1991 from the La Sapienza University of Rome.

From 1991 to 1998, she worked as a research fellow at the Regina

Elena Cancer Institute (Rome) and received her Specialty Board

Certification in Clinical Pathology from La Sapienza University

(1995). She joined the doctoral program in Molecular Medicine and

Endocrinology at the same University in 2001 and earned her PhD in

2004. Since 2005, Dr. Iacobini is a Research Assistant in Endocri-

nology and Metabolism at the Department of Clinical and Molecular

Medicine of La Sapienza University of Rome. Dr. Iacobini ’ s research

activity focuses on the molecular mechanisms involved in the

pathogenesis of vascular and metabolic complications of diabetes

and the metabolic syndrome. She is author of 39 full papers pub-

lished in peer-reviewed journals and has been the recipient of one

prize conferred by the Italian Diabetes Society for her research on

diabetes and its complications.

Carlo Ricci, PhD, was born in Rome on 19 July, 1971. He received

his MSc in Biology in 1996 from La Sapienza University of Rome.

From 1996 to 1998, he worked as research fellow at the Department

of Cellular and Development Biology at La Sapienza University of

Rome. Then, he joined the doctoral program in Endocrinological,

Metabolic and Andrological Sciences at the same university in 2002

and earned his PhD in 2005. Since 2006, Dr. Ricci is a Research

Assistant in Endocrinology and Metabolism at the Department of

Clinical and Molecular Medicine of La Sapienza University of Rome.

His research activity is focused on the molecular mechanisms

involved in the pathogenesis of vascular and metabolic complica-

tions of diabetes and the metabolic syndrome. He is author of 19 full

papers published in peer-reviewed journals.

Claudia Blasetti Fantauzzi, PhD, was born in Avezzano (AQ) on 18

June, 1982. She received her Bachelor ’ s Degree with honors in

Biology in 2007 and her Master ’ s Degree with honors in Genetics

and Molecular Biology in 2009 from the La Sapienza University of

Rome. She joined the doctoral program in Molecular Medicine at

the same university in 2009 and during this period she wrote her

PhD thesis in the laboratory of Prof. Giuseppe Pugliese. She earned

her PhD in 2013 and in the same year she received the Teresa

Ariaudo award for a Postdoctoral fellowship by the Istituto Pasteur




– Fondazione Cenci Bolognetti, Rome. Dr. Blasetti Fantauzzi ’ s

research activity focuses on the molecular mechanisms involved

in the pathogenesis of vascular and metabolic complications of

diabetes and the metabolic syndrome. She is author of six papers

published in peer-reviewed journals and has been recipient of the

Parma Diabete 2012 and the Lidio Baschieri awards.

Stefano Menini, PhD, was born in Genoa on 4 November, 1967.

He received his MSc in Biology (1995, cum laude) and the PhD in

Biology and Pathology of Aging (2000) from the University of Genoa.

He also earned a MSc in Human Nutrition (2003, cum laude) from

the Tor Vergata University of Rome. Formerly, he was a Research

Assistant in Pathology at the University of Genoa and in Endocri-

nology and Metabolism at La Sapienza University of Rome. Dr.

Menini is Senior Investigator in Endocrinology and Metabolism at

the Department of Clinical and Molecular Medicine of La Sapienza

University of Rome. He conducts research in the field of diabetes

and the metabolic syndrome investigating the role of the receptors

for the advanced glycation endproducts in vascular and metabolic

complications of these disorders, mainly focusing on galectin-3

biology and function. He is author of 47 full papers published in

peer-reviewed journals and has been recipient of two prizes con-

ferred for his research on diabetes and its complications.



Date post:	20-Nov-2023
Category:	Documents
Upload:	independent
View:	0 times
Download:	0 times

Galectin-3 in diabetic patients

Documents