Post on 11-Feb-2022
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Mimecan and cardiac extracellular matrix integrityLucas Van Aelst, MD
Department of Internal Medicine, University Hospitals Leuven, Leuven, BelgiumVIB-Vesalius Research Center, KULeuven, Leuven, Belgium
What is mimecan?
• Synonym: Osteoglycin (OGN)
• Part of the Small Leucin-Rich ProteoGlycans (SLRP)Other members: biglycan, decorin, fibromodulin, lumican
Phylogenetic analysis and chromosomal organization of
various human SLRP classes.
Schaefer, Iozzo J Biol Chem 2008;283:21305
Small Leucin-Rich Proteoglycans
Multiple signaling pathways evoked by SLRPs
Schaefer, Iozzo J Biol Chem 2008;283:21305
Iozzo J Biol Chem 1999;274:18843
Important for regulation of matrix structure, cell cycle and growth actions
Matricellular proteinsModulate cell-matrix interactions and cell function, without participating
in structural scaffold of the extracellular matrix.
Members:
CCN family members (CCN1-6),Osteonectin (SPARC),Osteopontin (OPN),Tenascins (TN-C, TN-X),Thrombospondins (TSP-1, TSP-2)
Prenatal Growth Adult life Pathology
BIRTH
Tissue repair,Tumour growth
Time
Exp
ress
ion
leve
l
Known non-cardiac functions of mimecan
• Studied in: 1990: Bone formation (Bentz et al., J Biol Chem 265:5024),1997: Atherosclerosis (Shanahan et al., Arterioscler Thromb Vasc Biol 17:2437),1998: Eye & corneal transparency (Liu et al., J Biol Chem 273:22584),2005: Pituitary tumours (Hu et al., J Clin Endocrin Metab 90;6657), 2008: Cochlea & auditory phenotype (Williamson et al., Hear Res 237:57),2008: Metastasis (Cui et al., Acta Biochim Biophys Sin 40:349), 2009: Arteriogenesis (Kampmann et al., Mol Cell Biochem 322:15),2009: Differentiation SCLC(-)/NSCLC(+) (Zhang et al., Oncol Rep 22:1057), 2010: Metabolic syndrome (Pravenec. Methods Mol Biol 597:415),2010: (Pre)term labour (Romero et al., J Matern Fetal Neonatal Med 23:261).
Osteoglycin protein expression in human heart disease
CAD: Isolated coronary artery disease;AS: Concentric hypertrophy secondary to aortic stenosis;HF: Ischemic heart failure and eccentric hypertrophy;HTN: Hypertensive heart disease
Petretto et al., Nat Genet 2008;40(5):546
Does mimecan regulate the integrity of the cardiac extracellular matrix
after myocardial infarction?
0
5
10
15
20
25
30
Sham 3d post-MI 7d post-MI 14d post-MI
• mRNA: Myocardial infarction in mice, sacrificed after 3d, 7d, 14d
p < 0,05
p < 0,05
p = 0,05
Re
lati
ve e
xpre
ssio
n le
vel (
A.U
)
p = NS
Increased expression of mimecan in infarcted area
Van Aelst, unpublished
p < 0,05
0
0,5
1
1,5
2
2,5
3
3,5
Sham 3d post-MI 14d post-MI
Protein:
• Infarcted Area • Remote Area
Increased expression of mimecan in infarcted area
PreOGN
OGNGAPDH
p = NS
p < 0,05
p < 0,05
Re
lati
ve e
xpre
ssio
n le
vel (
A.U
)
Van Aelst, unpublished
Infarcted AreaRemote Area
R
I
S
BB
Increased mortality in the absence of mimecan
Myocardial infarction, mimecan-KO vs. WT mice, 14 days
Similar infarct size in WT vs. KO
Surv
ival
Days after myocardial infarction
Male WT (n = 7)
Female WT (n = 14)
Female KO (n = 8)
Male KO (n = 13)
0
10
20
30
40
50
WT KO
Infa
rct
Size
(%
)
Van Aelst, unpublished
*
* p < 0,05
Cardiac rupture and dilatation in the absence of mimecan in male mice
Mimecan WT, MI, 3d Mimecan KO, MI, 3d
Van Aelst, unpublished
No difference in diastolic dimension nor cardiac function 14d after MI in WT vs KO mice
0
1
2
3
4
5
6
7
WT KO WT KO
LVID
d -
len
gth
(m
m)
0
5
10
15
20
25
30
35
WT KO WT KO
Frac
tio
nal
sh
ort
en
ing
(%)
Van Aelst, unpublished
WT: n = 14KO: n = 8
Baseline 14d after MI Baseline 14d after MI
No significant differences in inflammatory and basic structural histological analyses between WT and KO animals
0
250
500
750
WT KO
CD
45
co
un
t/m
m² WT, 14d KO, 14d
Infarct Thickness (µm) 316 ± 17 281 ± 18
Res. Necrotic Area (%) 4,9 ± 0,5 4,0 ± 0,9
Mac3 count/mm² 131 ± 25 141 ± 35
CD31 count/mm² 151 ± 14 177 ± 20
CD45, WT CD45, KO
Van Aelst, unpublished
No obvious difference in total collagen content in the infarcted area between WT and KO mice
0
10
20
30
40
50
60
WT KO
Co
llage
n D
ep
osi
tio
n (
%)
WT
KO
Van Aelst, unpublished
Impaired collagen cross-linking in the infarct in the absence of mimecan
% Thick/thin collagen fibers:
33 ± 3.4% Thick/thin collagen fibers:
18 ± 4.3* *P<0.01
MIMECAN WILD TYPE MIMECAN KNOCKOUT
Van Aelst, unpublished
Mimecan treatment prevents cardiac dilatation and dysfunction
0
10
20
30
40
RR5 - no MMI
OGN - no MMI
RR5 -MMI
OGN -MMI
Eje
ctio
n F
ract
ion
(%
)
0
1
2
3
4
5
6
7
RR5 - no MMI
OGN - no MMI
RR5 - MMIOGN -MMI
LVID
d (
mm
)
I.V. injection of 1.109 AdV Mimecan, 7 d before MI in WT mice
high mimecan plasma/cardiac levels
p < 0,05 p < 0,05
RR5Sham
RR5Sham
OGNSham
OGNSham
RR5MI
RR5MI
OGNMI
OGNMI
Vector:Group:
Vector:Group:
Van Aelst, unpublishedn = 5 n = 5 n = 10 n = 10
Conclusion:• Matricellular proteins modulate cell-matrix interactions and cell
function, without participating in the structural scaffold of theextracellular matrix (ECM).
• SLRPs, a recently described class of collagen-associated matrixproteins, have a role in collagen fibrillogenesis and a direct andindirect effect on cell growth. As such, they can be classified asmatricellular proteins.
• Mimecan KO male mice die between 3d and 10d after MI (rupture).
• In mimecan KO female mice, there is no significant difference inmortality and cardiac function as compared to WT female mice;there is a difference in collagen quality between mimrcan WT andKO female animals.
• Adenoviral overexpression of mimecan improves cardiac functionafter MI.
• Further in vitro studies are needed to establish the role of mimecanin cardiac ECM integrity after myocardial infarction.