首页> 美国卫生研究院文献>American Journal of Physiology - Heart and Circulatory Physiology >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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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

机译:心脏受限的基质金属蛋白酶4的组织抑制剂的过表达或缺失:压力超负荷引起的肥大后对左心室结构和功能的差异作用

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摘要

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.
机译:从历史上看,基质金属蛋白酶(TIMPs)的组织抑制剂被认为是单色的。但是,最近观察到的左心室功能不全和基质重塑的差异性TIMP图谱表明,单个TIMPs的生物学作用更加多样化。这项研究检验了以下假设,即心脏特异性过表达(TIMP-4OE)或缺失(基因敲除; TIMP-4KO)会在压力超负荷(LVPO)后差异地影响LV功能和结构。用TIMP-4OE(n = 38),TIMP-4KO(n = 24)以及年龄/品系匹配的野生型在小鼠(年龄3.5±0.1 mo,性别分布相同)小鼠中诱发LVPO(横向主动脉缩窄)类型(WT,n = 25),从而在LVPO后28天确定LV重塑和功能指标,例如LV质量和射血分数(LVEF)。 LVPO后,TIMP-4KO组的早期(7天)和晚期(28天)存活率降低了约25%(P <0.05)。尽管LVPO在所有组中均增加了LV质量,但TIMP-4OE减弱了相对肥厚的反应。对于LVPO,WT和TIMP-4KO之间的LVEF相似(分别为48±2%和45±3%),而对于TIMP-4OE则更高(57±2%,P <0.05)。使用LVPO,所有组的LV心肌胶原蛋白表达(I,III型)均增加了三倍(P <0.05),但令人惊讶的是,TIMP-4KO组的这种反应最强劲。这些独特的发现表明,在LVPO刺激下增加的心肌TIMP-4可能实际上对生存,LV功能和细胞外基质(ECM)重塑提供保护作用。这些发现挑战了经典的信念,即特定的心肌TIMPs(例如TIMP-4本身)水平升高,在病理刺激(例如LVPO)后导致不利的ECM积累。

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