Angiotensin II signaling pathways mediate expression of cardiac T-type calcium channels

Recent studies indicate that cardiac T-type Ca2+ current (I-CaT) reappears in hypertrophied ventricular cells. The aim of this study was to investigate the role of angiotensin II (Ang II), a major inducer of cardiac hypertrophy, in the reexpression of T-type channel in left ventricular hypertrophied myocytes. We induced cardiac hypertrophy in rats by abdominal aorta stenosis for 12 weeks and thereafter animals were treated for 2 weeks with losartan (12 mg/kg per day), an antagonist of type 1 Ang II receptors (AT(1)). In hypertrophied myocytes, we showed that the reexpressed I-CaT is generated by the Ca(V)3.1 and Ca(V)3.2 subunits. After losartan treatment, I-CaT density decreased from 0.40 +/- 0.05 pA/pF (n = 26) to 0.20 +/- 0.03 pA/pF (n = 27, P < 0.01), affecting Ca(V)3.1- and Ca(V)3.2- related currents. The amount of Ca(V)3.1 mRNA increased during hypertrophy and retrieved its nonhypertrophic level after losartan treatment, whereas the amount of Ca(V)3.2 mRNA was unaffected by stenosis. In cultured newborn ventricular cells, chronic Ang II application (0.1 μmol/L) also increased I-CaT density and Ca(V)3.1 mRNA amount. UO126, a mitogen-activated protein kinase kinase-1/2 ( MEK1/2) inhibitor, reduced Ang II - increased I-CaT density and Ca(V)3.1 mRNA amount. Bosentan, an endothelin ( ET) receptor antagonist, reduced Ang II - increased ICaT density without affecting the amount of Ca(V)3.1 mRNA. Finally, cotreatment with bosentan and UO126 abolished the Ang II - increased I-CaT density. Our results show that AT(1)-activated MEK pathway and autocrine ET-activated independent MEK pathway upregulate T-type channel expression. Ang II - increased of ICaT density observed in hypertrophied myocytes may play a role in the pathogenesis of Ca2+ overload and arrhythmias seen in cardiac pathology.