Published online before print April 26, 2007, doi: 10.1161/01.RES.0000268497.93085.e1
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Submitted on July 28, 2006
Revised on April 15, 2007
Accepted on April 18, 2007
Angiotensin II Increases Expression of 
1C 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 ;
From the Division of Cardiology (C.-T.T., J.-J.H., C.-S.H., K.-L.H., C.-D.T., L.-P.L., Y.-Z.T., F.-T.C., J.-L.L.), Department of Internal Medicine, National Taiwan University Hospital, Taipei; Institute of Biomedical Sciences (D.L.W.), Academia Sinica, Taipei; and Institute of Pharmacology (W.-P.C., L.-P.L.) and Department of Laboratory Medicine (F.-T.C.), National Taiwan University Hospital, Taipei, Taiwan.
* To whom correspondence should be addressed. E-mail: futienc{at}ha.mc.ntu.edu.tw.
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 
1C 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 1C 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 1C subunit gene promoter showed that cAMP response element (CRE) (-1853 to -1845) was an important cis element in Ang II-induced LCC 1C 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 1C 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 1C subunit expression and serine 133 phosphorylation of CREB, which were attenuated by oral losartan and simvastatin. In summary, Ang II induced LCC 1C subunit expression via a protein kinase C-, reactive oxygen species-, and CREB-dependent pathway and was blocked by losartan and simvastatin.
Key words: angiotensin II • dihydropyridine receptor
1C subunit •
transcriptional regulation •
signal transduction •
cAMP response element-binding protein
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