Mechanistic relationship between membrane type-1 matrix metalloproteinase and the myocardial response to pressure overload.
Mechanistic relationship between membrane type-1 matrix metalloproteinase and the myocardial response to pressure overload.
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DOI：
10.1161/circheartfailure.113.000984
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发表时间：
2014-03-01
期刊：
影响因子：
--
通讯作者：
Spinale FG
中科院分区：
文献类型：
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作者：
Zile MR;Baicu CF;Stroud RE;Van Laer AO;Jones JA;Patel R;Mukherjee R;Spinale FG
虽然基质金属蛋白酶（MMP）最初被认为主要导致细胞外基质降解，但某些MMP类型如膜1型MMP（MT 1-MMP）也可能通过潜伏相关转化生长因子（TGF）结合蛋白（LTBP-1）的水解和TGF依赖性促纤维化信号传导的激活参与促纤维化级联。本研究验证了MT 1-MMP在左心室（LV）压力超负荷（PO）刺激的基质重塑反应中起直接作用的假设。心脏限制性MT 1-MMP过表达（MT 1-OE）或MT 1-MMP表达降低（MT 1-RE）的野生型（WT）和转基因小鼠接受PO 4周。PO导致WT小鼠的LV质量增加57%（LV舒张末期容积无变化，导致LV质量/容积比增加，与向心性重构一致），MT 1-MMP介导的LTBP-1水解增加60%，胶原蛋白含量增加190%。虽然PO后WT、MT 1-OE和MT 1-RE之间的LV质量相似，但LV功能、MT 1-MMP介导的LTBP-1水解和胶原含量存在显著差异。与WT相比，MT 1-OE中的PO增加了LTBP-1水解（18%）、胶原含量（60%）、左心房尺寸（19%;指示LV舒张功能障碍）。与两种WT相比，MT 1-RE中的PO降低了LAD（19%）、LTBP-1水解（40%）和胶原蛋白含量（32%）。尽管PO刺激和LV心肌生长的幅度相等，但改变MT 1-MMP水平引起重构中的特定基质依赖性变化，从而证明在压力超负荷的适应不良重构和心肌纤维化反应的发展中的机械作用。
While matrix metalloproteinases (MMPs) were initially thought to primarily result in extracellular matrix degradation, certain MMP types such as membrane type-1 MMP (MT1-MMP) may also be involved in profibrotic cascades through hydrolysis of latency-associated transforming growth factor (TGF) binding protein (LTBP-1) and activation of TGF dependent profibrotic signaling. The present study tested the hypothesis that MT1-MMP plays a direct role in the matrix remodeling response to a left ventricular (LV) pressure overload (PO) stimulus. Wild-type (WT) and transgenic mice with cardiac restricted MT1-MMP over-expression (MT1-OE) or MT1-MMP reduced expression (MT1-RE) underwent PO for 4 weeks. PO resulted in a 57% increase in LV mass (no change in LV end diastolic volume, resulting in an increase in the LV mass / volume ratio consistent with concentric remodeling), a 60% increase in MT1-MMP mediated LTBP-1 hydrolysis, and a 190% increase in collagen content in WT mice. While LV mass was similar between WT, MT1-OE and MT1-RE following PO, significant differences in LV function, MT1-MMP mediated LTBP-1 hydrolysis and collagen content occurred. PO in MT1-OE increased LTBP-1 hydrolysis (18%) collagen content (60%), left atrial dimension (19%; indicative of LV diastolic dysfunction) compared with WT. PO in MT1-RE reduced LAD (19%), LTBP-1 hydrolysis (40%) and collagen content (32%) compared to both WT. Despite an equivalent PO stimulus and magnitude of LV myocardial growth, altering MT1-MMP levels caused specific matrix dependent changes in remodeling, thereby demonstrating a mechanistic role in the development of the maladaptive remodeling and myocardial fibrotic response to pressure-overload.