Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice

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. We compared LV function in young (69 months), middle-aged (1215 months), old (1824 months) and senescent (2634 months) wild-type (WT) and MMP-9 null mice (n epsilon 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- (TGF-)-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. MMP-9 deletion attenuates the age-related decline in diastolic function, in part by reducing TGF- signalling-induced periostin and CTGF expression and increasing MMP-8 expression to regulate myocardial collagen turnover and deposition.