Attenuation of ER stress prevents post-infarction-induced cardiac rupture and remodeling by modulating both cardiac apoptosis and fibrosis.
Attenuation of ER stress prevents post-infarction-induced cardiac rupture and remodeling by modulating both cardiac apoptosis and fibrosis.
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DOI：
10.1016/j.cbi.2014.10.032
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发表时间：
2015-01-05
影响因子：
5.1
通讯作者：
Yan L
中科院分区：
文献类型：
--
作者：
Luo T;Kim JK;Chen B;Abdel-Latif A;Kitakaze M;Yan L
内质网（ER）应激参与多种心血管疾病的病理生理过程，但ER应激在心肌梗死（MI）后心脏破裂和/或重构中的作用尚不清楚。在这里，我们研究了ER应激是否在小鼠的这些过程中起主要作用。我们结扎小鼠左冠状动脉（LCA）而不进行再灌注，并腹腔注射氯化钠或4-苯基丁酸（4-PBA，20 mg/kg/d）4周。心肌梗死第一周内心脏破裂率在对照组和4-PBA组分别为37.5%和18.2%。与对照组相比，4-PBA组室壁瘤和纤维化程度较轻，心功能较好。对照组心肌组织中ER应激标志物的蛋白水平在MI后的整个4周期间保持升高，而促凋亡蛋白主要在MI后的早期阶段增加，促纤维化蛋白在MI后的晚期阶段显著增加; 4-PBA降低所有这些蛋白水平。在原代培养的新生大鼠心肌细胞或成纤维细胞中，缺氧（3%O2）增加了心肌细胞凋亡的数量，并促进成纤维细胞的增殖和迁移，所有这些都被4-PBA（0.5 mM）减弱。这些研究结果表明，心肌梗死诱导ER应激并引发心脏细胞凋亡和纤维化，最终导致心脏破裂和重塑，减轻ER应激可能是预防心肌梗死后并发症的有效治疗目标。
Endoplasmic reticulum (ER) stress is implicated in the pathophysiology of various cardiovascular diseases, but the role of ER stress in cardiac rupture and/or remodeling after myocardial infarction (MI) is still unclear. Here we investigated whether ER stress plays a major role for these processes in mice. We ligated the left coronary artery (LCA) without reperfusion in mice and administered either NaCl or 4-phenylbutyric acid (4-PBA, 20 mg/kg/d) intraperitoneally for 4 weeks. Cardiac rupture rates during the first week of MI were 37.5% and 18.2% in the control and 4-PBA groups, respectively. The extent of ventricular aneurysm and fibrosis was less, and the cardiac function better, in the 4-PBA group compared with the control group. The protein levels of ER stress markers in the heart tissues of the control group remained elevated during the entire 4-week period after MI, while pro-apoptotic proteins mainly increased in the early phase, and the pro-fibrotic proteins markedly increased in the late phase post MI; 4-PBA decreased all of these protein levels. In the primary cultured neonatal rat cardiomyocytes or fibroblasts, hypoxia (3% O2) increased the number of apoptotic cardiomyocytes and promoted the proliferation and migration of fibroblasts, all of which were attenuated by 4-PBA (0.5 mM). These findings indicate that MI induces ER stress and provokes cardiac apoptosis and fibrosis, culminating in cardiac rupture and remodeling, and that the attenuation of ER stress could be an effective therapeutic target to prevent post-MI complications.