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

Abstract

Abstract-Recent studies indicate that cardiac T-type Ca 2ϩ 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 0.40Ϯ0.05 pA/pF (nϭ26) to 0.20Ϯ0.03 pA/pF (nϭ27, PϽ0.01), 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 mol/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 2ϩ overload and arrhythmias seen in cardiac pathology.

Beneficial Effects of the Dual L- and T-Type Ca2+ Channel Blocker Efonidipine on Cardiomyopathic Hamsters

“…6 As our data shows, in the golden hamsters the expression of the TCC (mRNA and protein) in cardiomyocytes was low, whereas in the UM-X7.1 cardiomyopathic hamster hearts the TCC was re-expressed during the development of HF. In the cardiomyopathic hamster, rat and feline, it is postulated that excessive Ca 2+ overload may be related to the abnormal expression of the TCC.…”

Caveolin-3 Regulates Protein Kinase A Modulation of the CaV3.2 (α1H) T-type Ca2+ Channels

“…The Ca v 3.1 and Ca v 3.2 isoforms are normally expressed in embryonic hearts (11,12), but postnatal expression of these isoforms diminishes with almost no expression in normal adult ventricular myocytes. However, the TTCCs are re-expressed during conditions of cardiac hypertrophy and heart failure and are reported to be associated with decreased cardiac function (13)(14)(15). Ca 2ϩ influx through the re-expressed voltage-gated Ca v 3.2 (␣ 1H ) TTCC is indicated to be responsible for inducing pathological cardiac hypertrophy in a pressure overload model (16).…”

T-type calcium channels are regulated by hypoxia/reoxygenation in ventricular myocytes

“…Multiple lines of evidence suggest that factors secreted at the site of injury can modulate the T-type calcium channel, such as growth hormone secreted by atrial tumor cells (50), endothelin-1 and IGF-I in ventricular myocytes (45), and PDGF in fibroblasts (48 (26), and angiotensin II (12). Transcription factors proposed to regulate Ca v 3.2 include hypoxia-inducible factor (HIF)-1␣ (7), neuron restrictive silencer factor (25,51), and Csx/Nkx2.5 (46).…”