Wang Wei, Wang Hao, Geng Qing-Xin, Wang Hua-Ting, Miao Wei, Cheng Bo, Zhao Di, Song Guang-Min, Leanne Groban, Zhao Zhuo
Department of Cardiovascular Surgery, Shandong University Qilu Hospital, Shandong, China.
Department of Cardiology, Shandong Provincial Chest Hospital, Shandong, China.
Hypertens Res. 2015 Dec;38(12):813-20. doi: 10.1038/hr.2015.85. Epub 2015 Jul 30.
Autophagy is activated in hypertension-induced cardiac hypertrophy. However, the mechanisms and significance of an activated autophagy are not clear. This study was designed to determine the role of atorvastatin (ATO) in cardiac autophagy and associated benefits on cardiac remodeling and left ventricular function in spontaneously hypertensive rats (SHRs). Twenty-eight male SHRs at 8 weeks of age were randomized to treatment with vehicle (saline solution; SHR+V) or ATO (SHR+ATO; 50 mg kg(-1) per day) for 6 or 12 months. Age-matched male Wistar-Kyoto (WKY) rats were used as normotensive controls. Cardiac magnetic resonance was used to evaluate cardiac function and structure. Compared with WKY rats, SHRs showed significant left ventricle (LV) dysfunction, remodeling and increases in cardiomyocyte size, which were all attenuated by 6 and 12 months of ATO treatment. Compared with WKY rats, autophagy was activated in the hearts of SHRs and this effect was amplified by chronic ATO treatment, particularly following 12 months of treatment. Protein expression levels of microtubule-associated protein-1 light chain 3-II and beclin-1, the biomarkers of an activated cardiac autophagy, were significantly elevated in ATO-treated versus vehicle-treated SHRs and control WKY rats. Cardiac Akt and phosphorylated mammalian target of rapamycin (mTOR) expression were also increased in the hearts of SHR versus WKY rats, and this effect was attenuated by ATO treatment. These findings suggest that ATO-mediated improvements in LV function and structure in SHRs may be, in part, through its regulation of cardiac autophagy via the Akt/mTOR pathway.
自噬在高血压诱导的心脏肥大中被激活。然而，自噬激活的机制和意义尚不清楚。本研究旨在确定阿托伐他汀（ATO）在自发性高血压大鼠（SHR）心脏自噬中的作用以及对心脏重塑和左心室功能的相关益处。将28只8周龄的雄性SHR随机分为接受载体（盐溶液；SHR+V）或ATO（SHR+ATO；每天50mg/kg）治疗6个月或12个月。年龄匹配的雄性Wistar-Kyoto（WKY）大鼠用作正常血压对照。采用心脏磁共振评估心脏功能和结构。与WKY大鼠相比，SHR表现出明显的左心室（LV）功能障碍、重塑和心肌细胞大小增加，而ATO治疗6个月和12个月均减轻了这些变化。与WKY大鼠相比，SHR心脏中的自噬被激活，慢性ATO治疗放大了这种效应，尤其是在治疗12个月后。与载体治疗的SHR和对照WKY大鼠相比，激活的心脏自噬生物标志物微管相关蛋白1轻链3-II和beclin-1的蛋白表达水平在ATO治疗的SHR中显著升高。与WKY大鼠相比，SHR心脏中Akt和磷酸化雷帕霉素哺乳动物靶蛋白（mTOR）的表达也增加，而ATO治疗减弱了这种效应。这些发现表明，ATO介导的SHR左心室功能和结构改善可能部分是通过其经由Akt/mTOR途径调节心脏自噬实现的。
