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.
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Zhao, H., Liao, Y., Minamino, T. et al. Inhibition of Cardiac Remodeling by Pravastatin Is Associated with Amelioration of Endoplasmic Reticulum Stress. Hypertens Res 31, 1977–1987 (2008). https://doi.org/10.1291/hypres.31.1977
- endoplasmic reticulum stress
- heart failure
- tumor necrosis factor α
Genome-wide translational reprogramming of genes important for myocyte functions in overload-induced heart failure
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