Jones Steven P, Teshima Yasushi, Akao Masaharu, Marbán Eduardo
Institute of Molecular Cardiobiology, The Johns Hopkins University School of Medicine, 720 Rutland Ave-Ross 844, Baltimore, Md 21205, USA.
Circ Res. 2003 Oct 17;93(8):697-9. doi: 10.1161/01.RES.0000097262.21507.DF. Epub 2003 Sep 25.
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can exert beneficial effects independently of serum cholesterol reduction by increasing the bioavailability of nitric oxide. However, it is unclear whether statins can exert such effects directly on cardiac myocytes and whether mitochondria are potential targets. Neonatal rat cardiac myocytes were cultured and subjected to oxidant stress (1 hour of 100 micromol/L H2O2). Mitochondrial membrane potential, a key determinant of cardiomyocyte viability, was assessed by flow cytometric analysis of tetramethylrhodamine ethyl ester (TMRE)-loaded cells. Hydrogen peroxide significantly reduced mitochondrial membrane potential. Incubation of the cardiac myocytes in simvastatin (> or =1 micromol/L) 1 hour before peroxide exposure significantly attenuated the loss of TMRE fluorescence. This effect was inhibited by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or the ATP-sensitive mitochondrial potassium channel (mitoKATP) blocker 5-hydroxydecanoate. Simvastatin attenuates mitochondrial membrane depolarization after exposure to oxidant stress. These findings provide primary evidence that myocytes can act as triggers and effectors in the cardioprotective cascade of simvastatin therapy. These results bear implications of statin therapy as a potential clinical application of pharmacological preconditioning.
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）可通过提高一氧化氮的生物利用度，独立于血清胆固醇降低发挥有益作用。然而，尚不清楚他汀类药物是否能直接对心肌细胞产生这种作用，以及线粒体是否为潜在靶点。培养新生大鼠心肌细胞并使其遭受氧化应激（100微摩尔/升过氧化氢处理1小时）。通过对负载四甲基罗丹明乙酯（TMRE）的细胞进行流式细胞术分析，评估心肌细胞活力的关键决定因素线粒体膜电位。过氧化氢显著降低线粒体膜电位。在过氧化氢暴露前1小时，将心肌细胞置于辛伐他汀（≥1微摩尔/升）中孵育，可显著减轻TMRE荧光的损失。一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME）或ATP敏感性线粒体钾通道（mitoKATP）阻滞剂5-羟基癸酸可抑制这种作用。辛伐他汀可减轻氧化应激暴露后的线粒体膜去极化。这些发现提供了初步证据，表明心肌细胞可作为辛伐他汀治疗心脏保护级联反应中的触发因素和效应器。这些结果表明他汀类药物治疗作为药理学预处理的潜在临床应用具有重要意义。
