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J. Biol. Chem., Vol. 279, Issue 37, 38797-38802, September 10, 2004

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Adenylyl Cyclase Type VI Gene Transfer Reduces Phospholamban Expression in Cardiac Myocytes via Activating Transcription Factor 3^*

Mei Hua Gao, Tong Tang, Tracy Guo, Shu Qiang Sun, James R. Feramisco, and H. Kirk Hammond¶

From the Department of Medicine, University of California, San Diego and the Veterans Affairs San Diego Healthcare System, San Diego, California 92161

Cardiac-directed expression of adenylyl cyclase type VI (AC_VI) increases stimulated cAMP production, improves heart function, and increases survival in cardiomyopathy. In contrast, pharmacological agents that increase intracellular levels of cAMP have detrimental effects on cardiac function and survival. We wondered whether effects that are independent of cAMP might be responsible for these salutary outcomes associated with AC_VI expression. We therefore conducted a series of experiments focused on how gene transcription is influenced by AC_VI in cultured neonatal rat cardiac myocytes, with a particular focus on genes that might influence cardiac function. We found that overexpression of AC_VI down-regulated mRNA and protein expression of phospholamban, an inhibitor of the sarcoplasmic reticulum Ca²⁺-ATPase. We determined that the cAMP-responsive-like element in the phospholamban (PLB) promoter was critical for down-regulation by AC_VI. Overexpression of AC_VI did not alter the expression of CREB, CREM, ATF1, ATF2, or ATF4 proteins. In contrast, overexpression of AC_VI increased expression of ATF3 protein, a suppressor of transcription. Following AC_VI gene transfer, when cardiac myocytes were stimulated with isoproterenol or NKH477, a water-soluble forskolin analog that directly stimulates AC, expression of ATF3 protein was increased even more, which correlated with reduced expression of PLB. We then showed that AC_VI-induced ATF3 protein binds to the cAMP-responsive-like element on the PLB promoter and that overexpression of ATF3 in cardiac myocytes inhibits PLB promoter activity. These findings indicate that AC_VI has effects on gene transcription that are not directly dependent on cAMP generation.

Received for publication, May 21, 2004 , and in revised form, June 25, 2004.

^* This work was supported by NHLBI Grant 1P01 HL66941 from the National Institutes of Health (to H. K. H. and J. R. F.) and a Department of Veterans Affairs merit award (to H. K. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: University of California, San Diego, Veterans Affairs San Diego Healthcare System, 111-A, 3350 La Jolla Village Dr., San Diego, CA 92161. Tel.: 858-552-8585 (ext. 3542); Fax: 858-642-6213; E-mail: khammond{at}ucsd.edu.

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