Abstract P222: T-Type Calcium Channels Regulate NFAT Signaling in Cardiomyocytes and Are Expressed in Chronic Hypoxic Right Ventricle
Alterations in intracellular calcium (Ca2+) have a significant impact on Ca2+ signaling, an integral part of the cardiac response to pathological conditions. The calcineurin/NFAT signaling pathway is a well established Ca2+ -dependent mechanism for transcriptional regulation of ventricular remodeling target genes. Although low voltage-activated T-type Ca2+ channels are not normally present in the adult myocardium, they reappear in conditions of hypertrophy and heart failure, where their functions remain poorly understood. To further investigate T-type Ca2+ channels, we have employed cultured neonatal rat ventricular myocytes (NRVM) and rat models of pulmonary hypertension that lead to right ventricular (RV) hypertrophy and heart failure. To assay for NFAT activation in cardiomyocytes, NRVM were infected with NFATc1-GFP and nuclear localization of GFP was measured. NFAT activation was markedly stimulated by over expressing the human Cav3.2 T-type Ca2+ channel cDNA in NRVM, and this activation was inhibited by cyclosporin A (a calcineurin inhibitor), by T-type selective concentrations of mibefradil and NiCl2, and in the absence of extracellular Ca2+. To investigate the up regulation of cardiac T-type Ca2+ channels in vivo, rats were maintained in chronic hypoxia, where they developed significantly elevated RV systolic pressure, RV hypertrophy and reduced cardiac output. Electrophysiological measurements revealed elevated membrane capacitance in RV myocytes indicative of RV hypertrophy, and T-type current density was also increased. Myocytes isolated from the RV of pulmonary hypertensive rats that displayed elevated T-type currents and RV dysfunction, also showed impaired contractility with decreased sensitivity to Ca2+. The results in NRVM suggest that T-type channels contribute to hypertrophic signaling via their interaction with calcineurin/NFAT signaling intermediaries. Furthermore, T-type channels are expressed in the RV during pulmonary hypertension where they influence RV myocyte contractility. Thus, when expressed in pathological conditions, T-type Ca2+ channels may play a dual role as a signaling intermediary, as well as a modifier of ventricular contractile function.
- © 2011 by American Heart Association, Inc.