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(Circulation Research. 2003;93:1241.)
© 2003 American Heart Association, Inc.

Cellular Biology

Angiotensin II Signaling Pathways Mediate Expression of Cardiac T-Type Calcium Channels

Laurent Ferron, Véronique Capuano, Yann Ruchon, Edith Deroubaix, Alain Coulombe, Jean-François Renaud

From the Remodelage Tissulaire et Fonctionnel, Hôpital Marie Lannelongue, Le Plessis Robinson, France.

Correspondence to Laurent Ferron, CNRS UMR 8078, Remodelage Tissulaire et Fonctionnel, Hôpital Marie Lannelongue, 133 avenue de la Résistance, 92350 Le Plessis Robinson, France. E-mail laurent.ferron{at}ccml.u-psud.fr

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 (AT₁). In hypertrophied myocytes, we showed that the reexpressed I_CaT is generated by the Ca_V3.1 and Ca_V3.2 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_V3.1- and Ca_V3.2-related currents. The amount of Ca_V3.1 mRNA increased during hypertrophy and retrieved its nonhypertrophic level after losartan treatment, whereas the amount of Ca_V3.2 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_V3.1 mRNA amount. UO126, a mitogen-activated protein kinase kinase-1/2 (MEK1/2) inhibitor, reduced Ang II–increased I_CaT density and Ca_V3.1 mRNA amount. Bosentan, an endothelin (ET) receptor antagonist, reduced Ang II–increased I_CaT density without affecting the amount of Ca_V3.1 mRNA. Finally, cotreatment with bosentan and UO126 abolished the Ang II–increased I_CaT density. Our results show that AT₁-activated MEK pathway and autocrine ET-activated independent MEK pathway upregulate T-type channel expression. Ang II–increased of I_CaT density observed in hypertrophied myocytes may play a role in the pathogenesis of Ca²⁺ overload and arrhythmias seen in cardiac pathology.

Key Words: angiotensin II • mitogen-activated protein kinase • T-type Ca²⁺ channel • cardiac hypertrophy • gene expression

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