51. Hypoxic induction of T-type Ca2+ channels in rat cardiac myocytes: role of HIF-1α and RhoA/ROCK signalling.
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González‐Rodríguez, P., Falcón, D., Castro, M. J., Ureña, J., López‐Barneo, J., and Castellano, A.
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MUSCLE cells ,PHYSIOLOGICAL effects of calcium ,HYPOXEMIA ,ARRHYTHMIA ,PHYSIOLOGICAL research - Abstract
Key points T-type Ca
2+ channels are expressed in the ventricular myocytes of the fetal and perinatal heart, but are downregulated as development progresses. However, these channels are re-expressed in adult cardiomyocytes under pathological conditions., Hypoxia induces the upregulation of the T-type Ca2+ channel Cav 3.2 mRNA in cardiac myocytes, whereas Cav 3.1 mRNA is not significantly altered., The effect of hypoxia on Cav 3.2 mRNA requires hypoxia inducible factor-1α (HIF-1α) stabilization and involves the small monomeric G-protein RhoA and its effector ROCKI., Our results suggest that the hypoxic regulation of the Cav 3.2 channels may be involved in the increased probability of developing arrhythmias observed in ischemic situations, and in the pathogenesis of diseases associated with hypoxic Ca2+ overload., Abstract T-type Ca2+ channels are expressed in the ventricular myocytes of the fetal and perinatal heart, but are normally downregulated as development progresses. Interestingly, however, these channels are re-expressed in adult cardiomyocytes under pathological conditions. We investigated low voltage-activated T-type Ca2+ channel regulation in hypoxia in rat cardiomyocytes. Molecular studies revealed that hypoxia induces the upregulation of Cav 3.2 mRNA, whereas Cav 3.1 mRNA is not significantly altered. The effect of hypoxia on Cav 3.2 mRNA was time- and dose-dependent, and required hypoxia inducible factor-1α (HIF-1α) stabilization. Patch-clamp recordings confirmed that T-type Ca2+ channel currents were upregulated in hypoxic conditions, and the addition of 50 μ m NiCl2 (a T-type channel blocker) demonstrated that the Cav 3.2 channel is responsible for this upregulation. This increase in current density was not accompanied by significant changes in the Cav 3.2 channel electrophysiological properties. The small monomeric G-protein RhoA and its effector Rho-associated kinase I (ROCKI), which are known to play important roles in cardiovascular physiology, were also upregulated in neonatal rat ventricular myocytes subjected to hypoxia. Pharmacological experiments indicated that both proteins were involved in the observed upregulation of the Cav 3.2 channel and the stabilization of HIF-1α that occurred in response to hypoxia. These results suggest a possible role for Cav 3.2 channels in the increased probability of developing arrhythmias observed in ischaemic situations, and in the pathogenesis of diseases associated with hypoxic Ca2+ overload. [ABSTRACT FROM AUTHOR]- Published
- 2015
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