Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice
Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice
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DOI：
10.1093/cvr/cvs275
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发表时间：
2012-12-01
影响因子：
10.8
通讯作者：
Lindsey, Merry L.
中科院分区：
文献类型：
--
作者：
Chiao, Ying Ann;Ramirez, Trevi A.;Lindsey, Merry L.
与年龄相关的舒张期功能障碍归因于被动僵硬增加，而被动僵硬由细胞外基质(ECM)调节。我们最近发现，细胞外基质(ECM)介体--基质金属蛋白酶-9(MMP9)在左心室(LV)随年龄增长而增加。因此，本研究的目的是确定基质金属蛋白酶-9在心脏老化中的作用。我们比较了年轻(69个月)、中年(1215个月)、老年(1824个月)和衰老(2634个月)野生型(WT)和基质金属蛋白酶-9缺失小鼠(12个/组)的左心功能。所有组都有相似的收缩分数和主动脉峰值速度，表明收缩功能不会因年龄或基质金属蛋白酶-9缺失而改变。与年轻对照组相比，老年和老年WT组二尖瓣充盈早期和晚期充盈速度的比率降低，而这种降低在MMP9缺失的小鼠中减弱。同时，MMP9基因敲除小鼠(n 5~6个/组)左室胶原含量的增加减少。为了分析这些变化的机制，我们用实时荧光定量聚合酶链式反应检测了84个ECM和黏附分子的mRNA表达水平(n 6/组)。促纤维化的骨膜蛋白和结缔组织生长因子(CTGF)的表达随着衰老而增加，转化生长因子(TGF)诱导的蛋白水平和Smad信号转导也是如此，这些增加被基质金属蛋白酶-9的缺失所钝化。在衰老过程中，基质金属蛋白酶-9的缺失也会导致基质金属蛋白酶-8的代偿性增加，基质金属蛋白酶-9的缺失可以通过减少转化生长因子信号诱导的Periostin和CTGF的表达，增加基质金属蛋白酶-8的表达来调节心肌胶原的更新和沉积，从而减轻与年龄相关的舒张期功能的下降。
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.