Maturana Andrés, Lenglet Sébastien, Python Magaly, Kuroda Shun'ichi, Rossier Michel F
Global-Edge Institute, Tokyo Institute of Technology, Yokohama 226-8502, Japan.
Endocrinology. 2009 Aug;150(8):3726-34. doi: 10.1210/en.2008-1727. Epub 2009 May 14.
The mineralocorticoid receptor is involved in the development of several cardiac dysfunctions, including lethal ventricular arrhythmias associated with heart failure or hyperaldosteronism, but the molecular mechanisms responsible for these effects remain to be clarified. Reexpression of low voltage-activated T-type calcium channels in ventricular myocytes together with other fetal genes during cardiac pathologies could confer automaticity to these cells and would represent a pro-arrhythmogenic condition if occurring in vivo. In the present study, we demonstrated that in isolated neonatal rat ventricular myocytes, corticosteroids selectively induced the expression of a particular isoform of T channel, Ca(V)3.2/alpha1H. This response was accompanied by an increase of the Ca(V)3.2 T-type current, identified with the patch clamp technique by its sensitivity to nickel, and a concomitant acceleration of the myocyte spontaneous contractions. Silencing Ca(V)3.2 expression markedly reduced the chronotropic response to steroids. Moreover, modulation of the frequency of cell contractions by different redox agents was independent of channel expression but involved a direct regulation of channel activity. Although oxidants increased both Ca(V)3.2 current amplitude and beating frequency, they decreased L-type channel activity. Reducing agents had the opposite effect on these parameters. In conclusion, the acceleration of ventricular myocyte spontaneous contractions induced by corticosteroids in vitro appears dependent on the expression of the Ca(V)3.2 T channel isoform and modulated by the redox potential of the cells. These results provide a molecular model that could explain the high incidence of arrhythmias observed in patients upon combination of inappropriate activation of the mineralocorticoid receptor and oxidative stress.
盐皮质激素受体参与多种心脏功能障碍的发生发展，包括与心力衰竭或醛固酮增多症相关的致死性室性心律失常，但其导致这些效应的分子机制仍有待阐明。在心脏病变过程中，心室肌细胞中低电压激活的T型钙通道与其他胎儿基因一起重新表达，可能赋予这些细胞自律性，如果在体内发生，将代表一种促心律失常状态。在本研究中，我们证明在分离的新生大鼠心室肌细胞中，皮质类固醇选择性诱导T通道特定亚型Ca(V)3.2/α1H的表达。这种反应伴随着Ca(V)3.2 T型电流的增加，通过膜片钳技术根据其对镍的敏感性鉴定该电流，同时心肌细胞自发收缩加速。沉默Ca(V)3.2表达显著降低了对类固醇的变时反应。此外，不同氧化还原剂对细胞收缩频率的调节与通道表达无关，但涉及对通道活性的直接调节。虽然氧化剂增加了Ca(V)3.2电流幅度和搏动频率，但它们降低了L型通道活性。还原剂对这些参数有相反的影响。总之，体外皮质类固醇诱导的心室肌细胞自发收缩加速似乎依赖于Ca(V)3.2 T通道亚型的表达，并受细胞氧化还原电位的调节。这些结果提供了一个分子模型，可以解释在盐皮质激素受体不适当激活与氧化应激共同作用的患者中观察到的心律失常的高发生率。
