Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice.
OBJECTIVE
Age-related diastolic dysfunction has been attributed to an increased passive stiffness, which is regulated by extracellular matrix (ECM). We recently showed that matrix metalloproteinase (MMP)-9, an ECM mediator, increases in the left ventricle (LV) with age. The aim of this study, accordingly, was to determine the role of MMP-9 in cardiac ageing.


RESULTS
We compared LV function in young (6-9 months), middle-aged (12-15 months), old (18-24 months) and senescent (26-34 months) wild-type (WT) and MMP-9 null mice (n ≥ 12/group). All groups had similar fractional shortenings and aortic peak velocities, indicating that systolic function was not altered by ageing or MMP-9 deletion. The mitral ratios of early to late diastolic filling velocities were reduced in old and senescent WT compared with young controls, and this reduction was attenuated in MMP-9 null mice. Concomitantly, the increase in LV collagen content was reduced in MMP-9 null mice (n = 5-6/group). To dissect the mechanisms of these changes, we evaluated the mRNA expression levels of 84 ECM and adhesion molecules by real-time qPCR (n = 6/group). The expression of pro-fibrotic periostin and connective tissue growth factor (CTGF) increased with senescence, as did transforming growth factor-β (TGF-β)-induced protein levels and Smad signalling, and these increases were blunted by MMP-9 deletion. In senescence, MMP-9 deletion also resulted in a compensatory increase in MMP-8.


CONCLUSIONS
MMP-9 deletion attenuates the age-related decline in diastolic function, in part by reducing TGF-β signalling-induced periostin and CTGF expression and increasing MMP-8 expression to regulate myocardial collagen turnover and deposition.
San Antonio Cardiovascular Proteomics Center, San Antonio, TX,  USA.
Ying Ann
YA
Chiao
Trevi A
TA
Ramirez
Rogelio
R
Zamilpa
S Michelle
SM
Okoronkwo
Qiuxia
Q
Dai
Jianhua
J
Zhang
Yu-Fang
YF
Jin
Merry L
ML
Lindsey
D000367:Age Factors; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001794:Blood Pressure; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D003971:Diastole; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D005838:Genotype; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D013599:Systole; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left
C526318:CCN2 protein, mouse; D015815:Cell Adhesion Molecules; C082838:Postn protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D003094:Collagen; C576328:MMP8 protein, mouse; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse