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Specific activation of the alternative cardiac promoter of Cacna1c by the mineralocorticoid receptor

Abstract : The mineralocorticoid receptor (MR) antagonists belong to the current therapeutic armamentarium for the management of cardiovascular diseases, but the mechanisms conferring their beneficial effects are still poorly understood. Part of these MR effects might be related to the L-type Cav1.2 Ca2+ channel expression regulation, critically involved in heart failure and hypertension. Here, we show that MR acts as a transcription factor triggering aldosterone signal into specific alternative 'cardiac' P1-promoter usage, given rise to long (Cav1.2-LNT) N-terminal transcripts. Aldosterone increases Cav1.2-LNT expression in cardiomyocytes in a time- and dose-dependent manner due to MR-dependent P1-promoter activity, through specific DNA sequence-MR interactions. This cis-regulatory mechanism induced a MR-dependent P1-promoter switch in vascular cells leading to a new Cav1.2-LNT molecular signature with reduced Ca2+ channel blocker sensitivity. These findings uncover Cav1.2-LNT as a specific mineralocorticoid target that might influence the therapeutic outcome of cardiovascular diseases.
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Submitted on : Sunday, September 2, 2018 - 1:15:08 AM
Last modification on : Friday, October 23, 2020 - 4:54:42 PM
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  • HAL Id : tel-01865832, version 1



Thássio Ricardo Ribeiro Mesquita. Specific activation of the alternative cardiac promoter of Cacna1c by the mineralocorticoid receptor. Cardiology and cardiovascular system. Université Paris Saclay (COmUE); Universidade Federal de Sergipe, 2017. English. ⟨NNT : 2017SACLS530⟩. ⟨tel-01865832⟩



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