Differential effects of atorvastatin on autophagy in ischemic and nonischemic myocardium in Ossabaw swine with metabolic syndrome.
Differential effects of atorvastatin on autophagy in ischemic and nonischemic myocardium in Ossabaw swine with metabolic syndrome.
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DOI：
10.1016/j.jtcvs.2014.07.104
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Sellke FW
中科院分区：
文献类型：
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作者：
Sabe AA;Elmadhun NY;Sadek AA;Chu LM;Bianchi C;Sellke FW
多形他汀类药物的围手术期给药与改善心脏手术后的预后有关。适应性自噬是一种高度保守的细胞过程，其允许消除功能失调的细胞组分以响应应激和在饥饿条件下的存活。我们试图研究他汀类药物阿托伐他汀对缺血性和非缺血性心肌自噬的影响，利用临床相关的猪代谢综合征模型。雄性Ossabaw猪饲喂常规饲料（n= 8）、高胆固醇饲料（n= 8）或高胆固醇饲料加补充阿托伐他汀（每日1.5 mg/kg）（n= 8）。14周后，所有动物均接受将淀粉样缩窄器手术放置到回旋冠状动脉以诱导慢性缺血。在饮食开始后6个月收获非缺血性和缺血性心肌，并进行蛋白质印迹。蛋白质印迹结果表明，在非缺血性心肌中，高胆固醇饮食导致自噬的统计学显著降低，如mTOR增加和几种必需的自噬标志物（包括Beclin-1、LC 3B-I和LC 3B-II）的积累所示。补充阿托伐他汀可防止这些变化，并导致自噬增加，如自噬通量标记物P62减少所示。在缺血心肌中，阿托伐他汀实际上具有相反的作用，如p62增加和LC 3B-I、LCB-II和LAMP-2蓄积所示，自噬通量降低。阿托伐他汀给药对缺血和非缺血心肌中的自噬具有不同的作用。在代谢综合征的背景下，阿托伐他汀刺激非缺血心肌的自噬，同时部分抑制缺血心肌的自噬。对自噬的差异调节可能部分解释了他汀类药物在缺血和非缺血心肌中的心脏保护作用，这些发现可能对心脏手术的设置有影响。
The perioperative administration of pleiomorphic statin drugs has been implicated in improving outcomes after cardiac surgery. Adaptive autophagy is a highly conserved cellular process that allows for the elimination of dysfunctional cell components in response to stress and survival under starving conditions. We sought to investigate the effects of the statin drug atorvastatin on autophagy in ischemic and non-ischemic myocardium utilizing a clinically relevant porcine model of metabolic syndrome. Male Ossabaw swine were fed a regular diet (n= 8), a high-cholesterol diet (n= 8) or a high-cholesterol diet with supplemental atorvastatin (1.5 mg/kg daily) (n= 8). After fourteen weeks all animals underwent surgical placement of an ameroid constrictor to the circumflex coronary artery to induce chronic ischemia. Non-ischemic and ischemic myocardium was harvested six months after initiation of the diet and processed for western blotting. Western blot results demonstrate that in the non-ischemic myocardium a high cholesterol diet resulted in a statistically significant decrease in autophagy as indicated by an increase in mTOR and the accumulation of several essential autophagy markers including Beclin-1, LC3B-I, and LC3B-II. Atorvastatin supplementation prevented these changes, and resulted in an increase in autophagy as indicated by a decrease in autophagy flux marker P62. In the ischemic myocardium atorvastatin actually had the opposite effect, with a decrease in autophagy flux as indicated by an increase in p62 and an accumulation of LC3B-I, LCB-II and LAMP-2. Atorvastatin administration has differential effects on autophagy in ischemic and non-ischemic myocardium. In the setting of metabolic syndrome, atorvastatin stimulates autophagy in non-ischemic myocardium while partly inhibiting autophagy in ischemic myocardium. The differential regulation on autophagy may, in part, explain the cardioprotective effect of statins in both ischemic and non-ischemic myocardium, and these findings may have implications in the setting of cardiac surgery.