Abstract 11543: Matrix Metalloproteinase-9 Deletion Attenuates Myocardial Fibrosis and Diastolic Dysfunction in Aging Mice
Aging is associated with a decline in diastolic function of the left ventricle (LV), while systolic function is relatively preserved. The extracellular matrix (ECM) composition regulates LV passive stiffness, a major determinant of diastolic function. Collagen deposition is reduced in the LV of matrix metalloproteinase-9 (MMP-9) null mice post-myocardial infarction, and we recently showed that MMP-9 levels increase in the LV and plasma of aging mice. However, the involvement of MMP-9 in cardiac aging has not been established. We tested the hypothesis that MMP-9 induces LV fibrosis and diastolic dysfunction in aging mice. Using 2-dimensional and doppler echocardiography, we compared LV function in young (6-8 months), middle-aged (12-15 months), old (18-24 months) and senescent (>25 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 preserved in aging mice and was not altered by MMP-9 deletion. The mitral ratios of early to late diastolic filling velocities (E/A ratios) were reduced in old and senescent WT, but not middle-aged (1.32±0.03), compared to young WT mice (1.28±0.03 in old and 1.18±0.02 in senescent vs 1.44±0.03 in young WT; p<0.05). Strikingly, MMP-9 null mice of all age groups showed similar E/A ratios, and old (1.48±0.03) and senescent (1.33±0.04) MMP-9 null mice had higher E/A ratios than their age-matched WT controls (both p<0.05). To dissect the underlying mechanisms of these changes in diastolic function, we evaluated the mRNA expression levels of 84 ECM and adhesion molecule genes by RT2 PCR array (Qiagen). The expression of periostin, a matricellular protein that stimulates collagen fibrillogenesis, was increased 85% in senescent WT mice compared to young controls. Interestingly, periostin expression was reduced 48% in senescent MMP-9 null mice compared to WT controls (n=6/group). Concomitantly, picrosirius red staining revealed reduced collagen content in the LV of senescent MMP-9 null mice compared to WT controls (n=3/group). In conclusion, MMP-9 deletion attenuates the age-related myocardial fibrosis and the decline in diastolic function, in part by reducing periostin expression to regulate collagen levels.
- © 2011 by American Heart Association, Inc.