Notícias

Banca de QUALIFICAÇÃO: THASSIO RICARDO RIBEIRO MESQUITA

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
DISCENTE: THASSIO RICARDO RIBEIRO MESQUITA
DATA: 01/08/2017
HORA: 08:00
LOCAL: Sala de videoconferência do RENORBIO, UFS.
TÍTULO: Specific activation of the alternative cardiac promoter of Cacna1c by the mineralocorticoid receptor.
PALAVRAS-CHAVES: L-type Ca2+ channel; aldosterone; mineralocorticoid receptor; heart; vascular smooth muscle cells.
PÁGINAS: 114
GRANDE ÁREA: Ciências Biológicas
ÁREA: Fisiologia
RESUMO:

The mineralocorticoid receptor (MR) antagonists belong to the current therapeutic
armamentarium for the treatment of cardiovascular diseases, but the mechanism of their
beneficial effects remains poorly understood. Part of the cardiovascular effects of MR are
due to the regulation of L-type Cav1.2 Ca2+ channel expression, which is generated by tissue-specific alternative promoters as a long 'cardiac' (Cav1.2-LNT) or a short 'vascular' (Cav1.2-
SNT) N-terminal transcripts. To analyze the molecular mechanisms by which aldosterone,
through MR, modulates Cav1.2 expression and function in a tissue-specific manner. Our
results reveal that MR acts as a transcription factor to translate aldosterone signal into specific
'cardiac' P1-promoter activation. In primary cultures of neonatal rat ventricular myocytes,
aldosterone exposure for 24 hours increased in a dose-dependent manner Cav1.2-LNT
expression at both mRNA and protein levels, correlating with enhanced dose-, time- and MR-dependent P1-promoter activity. In silico analysis and mutagenesis identified MR interaction
with both specific activating and repressing DNA binding elements on the P1-promoter. The
relevance of this regulation was confirmed in a transgenic mice harbouring the luciferase
reporter gene under the control of the rat P1-promoter. Moreover, we show that aldosterone
induces a MR-dependent P1-promoter switch in vascular cells, in which the Cav1.2-SNT is
normally the major transcript, leading to vascular contractile dysfunction and a new Cav1.2-
LNT molecular signature, notably with a reduction of sensitivity to the Ca2+ channel blocker,
nifedipine. Our results identify the Cav1.2-LNT as a new specific mineralocorticoid target,
shedding new light into the pathophysiological MR cis-regulatory mechanisms.


MEMBROS DA BANCA:
Presidente - 1333720 - DANIEL BADAUE PASSOS JUNIOR
Externo à Instituição - JADER DOS SANTOS CRUZ
Externo à Instituição - MARK WILLIAM CHAPLEAU
Notícia cadastrada em: 19/07/2017 14:47
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