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

Published on Dec 12, 2003in Circulation Research15.862
· DOI :10.1161/01.RES.0000106134.69300.B7
Laurent Ferron12
Estimated H-index: 12
Véronique Capuano4
Estimated H-index: 4
+ 3 AuthorsJean-François Renaud12
Estimated H-index: 12
Recent studies indicate that cardiac T-type Ca 2+ 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 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 I CaT 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 I CaT density observed in hypertrophied myocytes may play a role in the pathogenesis of Ca 2+ overload and arrhythmias seen in cardiac pathology.
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