Angiotensin II signaling pathways mediate expression of cardiac T-type calcium channels.
Recent studies indicate that cardiac T-type Ca2+ current (ICaT) 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 ICaT is generated by the CaV3.1 and CaV3.2 subunits. After losartan treatment, ICaT density decreased from 0.40+/-0.05 pA/pF (n=26) to 0.20+/-0.03 pA/pF (n=27, P<0.01), affecting CaV3.1- and CaV3.2-related currents. The amount of CaV3.1 mRNA increased during hypertrophy and retrieved its nonhypertrophic level after losartan treatment, whereas the amount of CaV3.2 mRNA was unaffected by stenosis. In cultured newborn ventricular cells, chronic Ang II application (0.1 micromol/L) also increased ICaT density and CaV3.1 mRNA amount. UO126, a mitogen-activated protein kinase kinase-1/2 (MEK1/2) inhibitor, reduced Ang II-increased ICaT density and CaV3.1 mRNA amount. Bosentan, an endothelin (ET) receptor antagonist, reduced Ang II-increased ICaT density without affecting the amount of CaV3.1 mRNA. Finally, cotreatment with bosentan and UO126 abolished the Ang II-increased ICaT 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 ICaT density observed in hypertrophied myocytes may play a role in the pathogenesis of Ca2+ overload and arrhythmias seen in cardiac pathology.
Ferron
Laurent
L
CNRS UMR 8078, Remodelage Tissulaire et Fonctionnel, Hôpital Marie Lannelongue, 133 avenue de la Résistance, 92350 Le Plessis Robinson, France. laurent.ferron@ccml.u-psud.fr
Capuano
Véronique
V
Ruchon
Yann
Y
Deroubaix
Edith
E
Coulombe
Alain
A
Renaud
Jean-François
JF
D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000831:Animals, Newborn; D000077300:Bosentan; D002070:Butadienes / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D003251:Constriction, Pathologic / Q000150:complications; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009532:Nickel / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000502:physiology; D017466:Receptors, Endothelin / Q000502:physiology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D002070:Butadienes; D020747:Calcium Channels, T-Type; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009570:Nitriles; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D017466:Receptors, Endothelin; D013449:Sulfonamides; C113580:U 0126; D000804:Angiotensin II; C086539:BQ 788; D009532:Nickel; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D019808:Losartan; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one