Novel mechanisms for caspase inhibition protecting cardiac function with chronic pressure overload.
Novel mechanisms for caspase inhibition protecting cardiac function with chronic pressure overload.
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DOI：
10.1007/s00395-012-0324-y
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发表时间：
2013-01
影响因子：
9.5
通讯作者：
Vatner DE
中科院分区：
文献类型：
--
作者：
Park M;Vatner SF;Yan L;Gao S;Yoon S;Lee GJ;Xie LH;Kitsis RN;Vatner DE
心肌细胞凋亡被认为是心力衰竭发病机制中的主要机制。因此，抑制细胞凋亡的操作被认为是通过维持心肌细胞数量来保护心脏功能。我们通过观察半胱天冬酶抑制剂（CI）对C57 BL/6小鼠心脏结构和功能的影响来验证这一假设。与载体相比，CI保留了TAC后的左心室（LV）功能。TAC增加非心肌细胞的凋亡比在心肌细胞和这些增加钝在非心肌细胞CI。然而，总的肌细胞数，并没有显着差异之间的控制和TAC组和有没有相关性之间的肌细胞数量和细胞凋亡，但有很强的相关性之间的肌细胞数量和肌细胞增殖指数，Ki 67阳性肌细胞。尽管压力梯度相当，但CI组的LV肥大较少，可能归因于室壁应力降低。由于肌细胞数量的变化不能解释TAC的保护作用，因此确定了其他几种CI介导的机制，包括：（a）减轻TAC诱导的纤维化，（B）增强分离的肌细胞收缩性，和（c）增加的血管生成和Ki 67阳性肌细胞，这几乎完全是由于CI的非肌细胞凋亡，而不是肌细胞凋亡。CI在TAC后维持LV功能不是通过保护免受肌细胞损失，而是通过增强肌细胞收缩功能、肌细胞增殖和血管生成，导致LV壁应力降低、肥大和纤维化。
Myocyte apoptosis is considered a major mechanism in the pathogenesis of heart failure. Accordingly, manipulations that inhibit apoptosis are assumed to preserve cardiac function by maintaining myocyte numbers. We tested this assumption by examining the effects of caspase inhibition (CI) on cardiac structure and function in C57BL/6 mouse with pressure overload model induced by transverse aortic constriction (TAC). CI preserved left ventricular (LV) function following TAC compared with the vehicle. TAC increased apoptosis in non-myocytes more than in myocytes and these increases were blunted more in non-myocytes by CI. Total myocyte number, however, did not differ significantly among control and TAC groups and there was no correlation between myocyte number and apoptosis, but there was a strong correlation between myocyte number and an index of myocyte proliferation, Ki67-positive myocytes. Despite comparable pressure gradients, LV hypertrophy was less in the CI group, likely attributable to decreased wall stress. Since changes in myocyte numbers did not account for protection from TAC, several other CI-mediated mechanisms were identified including: (a) lessening of TAC-induced fibrosis, (b) augmentation of isolated myocyte contractility, and (c) increased angiogenesis and Ki67-positive myocytes, which were due almost entirely to the non-myocyte apoptosis, but not myocyte apoptosis, with CI. CI maintained LV function following TAC not by protecting against myocyte loss, but rather by augmenting myocyte contractile function, myocyte proliferation, and angiogenesis resulting in reduced LV wall stress, hypertrophy, and fibrosis.
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DOI：
10.1111/j.1440-1681.2009.05243.x
发表时间：
2009-11-01
影响因子：
2.9
作者：
Li, Xiao-Mei;Ma, Yi-Tong;Gao, Xiao-Ming
通讯作者：
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影响因子：
15.9
作者：
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通讯作者：
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影响因子：
37.8
作者：
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Lembo, G
DOI：
10.1073/pnas.0706406104
发表时间：
2007-11-06
影响因子：
11.1
作者：
Rota, Marcello;Kajstura, Jan;Anversa, Piero
通讯作者：
Anversa, Piero
影响因子：
24
作者：
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通讯作者：
Westaby, Stephen