Inhibition of Cardiac Remodeling by Pravastatin Is Associated with Amelioration of Endoplasmic Reticulum Stress
Inhibition of Cardiac Remodeling by Pravastatin Is Associated with Amelioration of Endoplasmic Reticulum Stress
复制标题
DOI：
10.1291/hypres.31.1977
复制
发表时间：
2008-10
影响因子：
5.4
通讯作者：
Hui Zhao;Y. Liao;T. Minamino;Y. Asano;M. Asakura;Jiyoong Kim;H. Asanuma;S. Takashima;M. Hori;M. Kitakaze
中科院分区：
文献类型：
--
作者：
Hui Zhao;Y. Liao;T. Minamino;Y. Asano;M. Asakura;Jiyoong Kim;H. Asanuma;S. Takashima;M. Hori;M. Kitakaze
本研究的目的是探讨普伐他汀是否能抑制压力超负荷或肿瘤坏死因子α(肿瘤坏死因子α)引起的内质网应激，抑制心脏重构。雄性C57BL/6J小鼠于造模后第2天开始灌胃普伐他汀(5 mg/kg/d)或单用赋形剂。在压力超负荷的心脏和用肿瘤坏死因子α处理的培养心肌细胞中，也研究了内质网应激信号通路。在TAC治疗4周后，普伐他汀治疗显著降低了心脏/体重和肺/体重比，并增加了左室短轴缩短率(LV)。内质网应激的标志，如ER伴侣和C/EBP同源蛋白(CHOP)的表达增加，以及反磷酸化真核细胞起始因子2α(eIF2α)的磷酸化增强，而普伐他汀治疗显著减弱了这些变化。普伐他汀治疗的TAC小鼠也显示出较少的心肌细胞凋亡。普伐他汀可显著抑制肿瘤坏死因子α在培养的乳鼠心肌细胞中的表达，并可明显抑制肿瘤坏死因子α对培养的新生大鼠心肌细胞的内质网应激。这些发现表明，普伐他汀抑制压力超负荷小鼠的心脏重构，这一作用与抑制内质网应激信号通路有关。
The aim of this study is to investigate whether pravastatin can inhibit cardiac remodeling and ameliorate endoplasmic reticulum (ER) stress caused by pressure overload or tumor necrosis factor α (TNFα). Either pravastatin (5 mg/kg/d) or vehicle alone was orally administered to male C57BL/6J mice from day 2 after a transverse aortic constriction (TAC) was performed. The ER stress signaling pathway was also studied in pressure-overloaded hearts and in cultured cardiomyocytes treated with TNFα . Four weeks after TAC, pravastatin treatment significantly reduced heart/body weight and lung/body weight ratios and increased left ventricular (LV) fractional shortening compared with the TAC alone. Markers of ER stress, such as increases in ER chaperone and C/EBP homologous protein (CHOP) expression and enhanced phosphorylation of antiphospho-eukaryotic initiation factor 2α (eIF2α), were observed in the hearts of TAC mice, while pravastatin treatment significantly blunted these changes. Pravastatin-treated TAC mice also showed less cardiac apoptosis. Cardiac expression of TNFα was increased in TAC mice, and TNFα induced ER stress in cultured neonatal rat cardiomyocytes, either of which was significantly inhibited by pravastatin. These findings indicate that pravastatin inhibits cardiac remodeling in mice subjected to pressure overload, and that this action is associated with inhibition of the ER stress signaling pathway.