Perrier Emeline, Kerfant Benoît-Gilles, Lalevee Nathalie, Bideaux Patrice, Rossier Michel F, Richard Sylvain, Gómez Ana María, Benitah Jean-Pierre
INSERM U637-EA3759, IFR3, Montpellier, France.
Circulation. 2004 Aug 17;110(7):776-83. doi: 10.1161/01.CIR.0000138973.55605.38. Epub 2004 Aug 2.
Cardiac hypertrophy underlies arrhythmias and sudden death, for which mineralocorticoid receptor (MR) activity has recently been implicated. We sought to establish the sequence of ionic events that link the initiating insult and MR to hypertrophy development.
Using whole-cell, patch-clamp and quantitative reverse transcription-polymerase chain reaction techniques on right ventricular myocytes of a myocardial infarction (MI) rat model, we examined the cellular response over time. One week after MI, no sign of cellular hypertrophy was found, but action potential duration (APD) was lengthened. Both an increase in Ca2+ current (I(Ca)) and a decrease in K+ transient outward current (I(to)) underlay this effect. Consistently, the relative expression of mRNA coding for the Ca2+ channel alpha1C subunit (Ca(v)1.2) increased, and that of the K+ channel K(v)4.2 subunit decreased. Three weeks after MI, AP prolongation endured, whereas cellular hypertrophy developed. I(Ca) density, Ca(v)1.2, and K(v)4.2 mRNA levels regained control levels, but I(to) density remained reduced. Long-term treatment with RU28318, an MR antagonist, prevented this electrical remodeling. In a different etiologic model of abdominal aortic constriction, we confirmed that APD prolongation and modifications of ionic currents precede cellular hypertrophy.
Electrical remodeling, which is triggered at least in part by MR activation, is an initial, early cellular response to hypertrophic insults.
心脏肥大是心律失常和猝死的基础，最近发现盐皮质激素受体（MR）活性与之有关。我们试图确定将起始损伤与MR联系到肥大发展的离子事件序列。
利用全细胞、膜片钳和定量逆转录-聚合酶链反应技术，对心肌梗死（MI）大鼠模型的右心室肌细胞进行研究，我们随时间检查细胞反应。MI后1周，未发现细胞肥大迹象，但动作电位时程（APD）延长。Ca2+电流（I(Ca)）增加和K+瞬时外向电流（I(to)）减少共同导致了这种效应。一致地，编码Ca2+通道α1C亚基（Ca(v)1.2）的mRNA相对表达增加，而K+通道K(v)4.2亚基的相对表达减少。MI后3周，AP延长持续存在，而细胞肥大出现。I(Ca)密度、Ca(v)1.2和K(v)4.2 mRNA水平恢复到对照水平，但I(to)密度仍降低。用MR拮抗剂RU28318长期治疗可防止这种电重构。在腹主动脉缩窄的另一种病因模型中，我们证实APD延长和离子电流改变先于细胞肥大。
电重构至少部分由MR激活触发，是对肥大性损伤的一种初始、早期细胞反应。
