Cho Kyoung-Im, Cha Tae-Joon, Lee Su-Jin, Shim In-Kyeung, Zhang Yin Hua, Heo Jung-Ho, Kim Hyun-Su, Kim Sung Joon, Kim Kyoung-Lyoung, Lee Jae-Woo
Cardiovascular Research Institute, Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea.
Department of Physiology, Seoul National University College of Medicine, Seoul, South Korea.
PLoS One. 2014 Oct 16;9(10):e106570. doi: 10.1371/journal.pone.0106570. eCollection 2014.
Statins, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, are associated with the prevention of atrial fibrillation (AF) by pleiotropic effects. Recent clinical trial studies have demonstrated conflicting results on anti-arrhythmia between lipophilic and hydrophilic statins. However, the underlying mechanisms responsible for anti-arrhythmogenic effects of statins are largely unexplored. In this study, we evaluated the different roles of lipophilic and hydrophilic statins (simvastatin and pravastatin, respectively) in acetylcholine (100 µM)-activated K+ current (IKACh, recorded by nystatin-perforated whole cell patch clamp technique) which are important for AF initiation and maintenance in mouse atrial cardiomyocytes. Our results showed that simvastatin (1-10 µM) inhibited both peak and quasi-steady-state IKACh in a dose-dependent manner. In contrast, pravastatin (10 µM) had no effect on IKACh. Supplementation of substrates for the synthesis of cholesterol (mevalonate, geranylgeranyl pyrophosphate or farnesyl pyrophosphate) did not reverse the effect of simvastatin on IKACh, suggesting a cholesterol-independent effect on IKACh. Furthermore, supplementation of phosphatidylinositol 4,5-bisphosphate, extracellular perfusion of phospholipase C inhibitor or a protein kinase C (PKC) inhibitor had no effect on the inhibitory activity of simvastatin on IKACh. Simvastatin also inhibits adenosine activated IKACh, however, simvastatin does not inhibit IKACh after activated by intracellular loading of GTP gamma S. Importantly, shortening of the action potential duration by acetylcholine was restored by simvastatin but not by pravastatin. Together, these findings demonstrate that lipophilic statins but not hydrophilic statins attenuate IKACh in atrial cardiomyocytes via a mechanism that is independent of cholesterol synthesis or PKC pathway, but may be via the blockade of acetylcholine binding site. Our results may provide important background information for the use of statins in patients with AF.
他汀类药物，即3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，通过多效性作用与心房颤动（AF）的预防相关。最近的临床试验研究在亲脂性和亲水性他汀类药物的抗心律失常作用方面显示出相互矛盾的结果。然而，他汀类药物抗心律失常作用的潜在机制在很大程度上尚未得到探索。在本研究中，我们评估了亲脂性和亲水性他汀类药物（分别为辛伐他汀和普伐他汀）在乙酰胆碱（100 μM）激活的钾电流（IKACh，通过制霉菌素穿孔全细胞膜片钳技术记录）中的不同作用，该电流对小鼠心房心肌细胞中AF 的起始和维持很重要。我们的结果表明，辛伐他汀（1-10 μM）以剂量依赖性方式抑制IKACh 的峰值和准稳态。相比之下，普伐他汀（10 μM）对IKACh 没有影响。补充胆固醇合成底物（甲羟戊酸、香叶基香叶基焦磷酸或法尼基焦磷酸）并不能逆转辛伐他汀对IKACh 的作用，表明对IKACh 有不依赖胆固醇的作用。此外，补充磷脂酰肌醇4,5-二磷酸、细胞外灌注磷脂酶C 抑制剂或蛋白激酶C（PKC）抑制剂对辛伐他汀对IKACh 的抑制活性没有影响。辛伐他汀还抑制腺苷激活的IKACh，然而，辛伐他汀在通过细胞内加载GTPγS 激活后不抑制IKACh。重要的是，辛伐他汀可恢复乙酰胆碱引起的动作电位时程缩短，而普伐他汀则不能。总之，这些发现表明亲脂性他汀类药物而非亲水性他汀类药物通过一种独立于胆固醇合成或PKC 途径的机制减弱心房心肌细胞中的IKACh，但可能是通过阻断乙酰胆碱结合位点。我们的结果可能为AF 患者使用他汀类药物提供重要的背景信息。
