Angiotensin II increases expression of α1C subunit of L-type calcium channel through a reactive oxygen species and cAMP response element-binding protein-dependent pathway in HL-1 myocytes

Chia Ti Tsai, Danny Ling Wang, Wen Pin Chen, Juey Jen Hwang, Chia Shan Hsieh, Kuan Lih Hsu, Chuen Den Tseng, Ling Ping Lai, Yung Zu Tseng, Fu Tien Chiang, Jiunn Lee Lin

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70 引文 斯高帕斯(Scopus)

摘要

Angiotensin II (Ang II) is involved in the pathogenesis of atrial fibrillation (AF). L-type calcium channel (LCC) expression is altered in AF remodeling. We investigated whether Ang II modulates LCC current through transcriptional regulation, by using murine atrial HL-1 cells, which have a spontaneous calcium transient, and an in vivo rat model. Ang II increased LCC α1C subunit mRNA and protein levels and LCC current density, which resulted in an augmented calcium transient in atrial myocytes. An ≈2-kb promoter region of LCC α1C subunit gene was cloned to the pGL3 luciferase vector. Ang II significantly increased promoter activity in a concentration- and time-dependent manner. Truncation and mutational analysis of the LCC α1C subunit gene promoter showed that cAMP response element (CRE) (-1853 to -1845) was an important cis element in Ang II-induced LCC α1C subunit gene expression. Transfection of dominant-negative CRE binding protein (CREB) (pCMV-CREBS133A) abolished the Ang II effect. Ang II (1 μmol/L, 2 hours) induced serine 133 phosphorylation of CREB and binding of CREB to CRE and increased LCC α1C subunit gene promoter activity through a protein kinase C/NADPH oxidase/reactive oxygen species pathway, which was blocked by the Ang II type 1 receptor blocker losartan and the antioxidant simvastatin. In the rat model, Ang II infusion increased LCC α1C subunit expression and serine 133 phosphorylation of CREB, which were attenuated by oral losartan and simvastatin. In summary, Ang II induced LCC α1C subunit expression via a protein kinase C-, reactive oxygen species-, and CREB-dependent pathway and was blocked by losartan and simvastatin.
原文英語
頁(從 - 到)1476-1485
頁數10
期刊Circulation Research
100
發行號10
DOIs
出版狀態已發佈 - 五月 1 2007
對外發佈

Keywords

  • Angiotensin II
  • cAMP response element-binding protein
  • Dihydropyridine receptor α 1C subunit
  • Signal transduction
  • Transcriptional regulation

ASJC Scopus subject areas

  • 生理學
  • 心臟病學與心血管醫學

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