Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy.
Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy.
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DOI：
10.1152/ajpheart.00063.2014
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发表时间：
2014-09
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通讯作者：
W. Yarbrough;C. Baicu;R. Mukherjee;An O. Van Laer;William T. Rivers;R. A. McKinney;Corey B Prescott;Robert E. Stroud;Parker D. Freels;Kia N. Zellars;M. Zile;F. Spinale
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文献类型：
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作者：
W. Yarbrough;C. Baicu;R. Mukherjee;An O. Van Laer;William T. Rivers;R. A. McKinney;Corey B Prescott;Robert E. Stroud;Parker D. Freels;Kia N. Zellars;M. Zile;F. Spinale
在历史上，基质金属蛋白酶(TIMPs)的组织抑制物被认为是功能单色的。然而，最近观察到的左心室(LV)功能障碍和基质重构的不同TIMP图谱表明，个体TIMP的生物学作用更加多样化。本研究验证了心脏特异性过表达(TIMP-4OE)或缺失(敲除；TIMP-4KO)会对压力超负荷(LVPO)后的左心功能和结构产生不同影响的假说。用TIMP-4OE(n=38)、TIMP-4KO(n=24)和年龄/应变匹配野生型(WT，n=25)诱导小鼠(年龄3.5±0.1mo，性别分布均为)，于LVPO后28d测定左心室重构和功能指标，包括左心室重量和射血分数(LVEF)。LVPO后，TIMP-4KO组早期(7天)和晚期(28天)存活率均降低约25%(P<；0.05)。在LVPO增加各组LV质量的同时，TIMP-4OE可使相对肥厚反应减弱。对于LVPO，西药组和TIMP-4KO组的LVEF相似(分别为48±2%和45±3%)，但高于TIMP-4OE组(57±2%，P<0.05)。有了LVPO，所有组的LV心肌胶原表达(I型、III型)都增加了三倍(P<；0.05)，但令人惊讶的是，这种反应在TIMP-4KO组中最为强烈。这些独特的发现表明，在LVPO刺激的背景下，增加的心肌TIMP-4实际上可能在存活、左心功能和细胞外基质(ECM)重塑方面提供保护作用。这些发现挑战了经典的观点，即特定心肌TIMP水平的增加，如TIMP-4本身，有助于病理性刺激(如LVPO)后不利的ECM积聚。
Historically, the tissue inhibitors of matrix metalloproteinases (TIMPs) were considered monochromatic in function. However, differential TIMP profiles more recently observed with left ventricular (LV) dysfunction and matrix remodeling suggest more diverse biological roles for individual TIMPs. This study tested the hypothesis that cardiac-specific overexpression (TIMP-4OE) or deletion (knockout; TIMP-4KO) would differentially affect LV function and structure following pressure overload (LVPO). LVPO (transverse aortic constriction) was induced in mice (3.5 ± 0.1 mo of age, equal sex distribution) with TIMP-4OE (n = 38), TIMP-4KO (n = 24), as well as age/strain-matched wild type (WT, n = 25), whereby indexes of LV remodeling and function such as LV mass and ejection fraction (LVEF) were determined at 28 days following LVPO. Following LVPO, both early (7 days) and late (28 days) survival was ~25% lower in the TIMP-4KO group (P < 0.05). While LVPO increased LV mass in all groups, the relative hypertrophic response was attenuated with TIMP-4OE. With LVPO, LVEF was similar between WT and TIMP-4KO (48 ± 2% and 45 ± 3%, respectively) but was higher with TIMP-4OE (57 ± 2%, P < 0.05). With LVPO, LV myocardial collagen expression (type I, III) increased by threefold in all groups (P < 0.05), but surprisingly this response was most robust in the TIMP-4KO group. These unique findings suggest that increased myocardial TIMP-4 in the context of a LVPO stimulus may actually provide protective effects with respect to survival, LV function, and extracellular matrix (ECM) remodeling. These findings challenge the canonical belief that increased levels of specific myocardial TIMPs, such as TIMP-4 in and of themselves, contribute to adverse ECM accumulation following a pathological stimulus, such as LVPO.