Published Online
on September 24, 2007

A more recent version of this article appeared on October 16, 2007

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Submitted on February 27, 2007
Accepted on August 13, 2007

Disruption of Type 5 Adenylyl Cyclase Enhances Desensitization of Cyclic Adenosine Monophosphate Signal and Increases Akt Signal With Chronic Catecholamine Stress

Satoshi Okumura MD, PhD, Dorothy E. Vatner MD, Reiko Kurotani PhD, Yunzhe Bai MD, Shumin Gao MD, Zengrong Yuan MD, PhD, Kousaku Iwatsubo MD, PhD, Coskun Ulucan MD, PhD, Jun-ichi Kawabe MD, PhD, Kaushik Ghosh PhD, Stephen F. Vatner MD, and Yoshihiro Ishikawa MD, PhD^*

From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine and Medicine (Cardiology), University of Medicine and Dentistry of New Jersey, New Jersey Medical School (D.E.V., S.G., Z.Y., K.I., C.U., J.K., S.F.V., Y.I.), Newark; Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine (S.O., R.K., Y.B., C.U., Y.I.), Yokohama, Japan; and Department of Mathematical Sciences, New Jersey Institute of Technology (K.G.), Newark.

^* To whom correspondence should be addressed. E-mail: ishikayo{at}umdnj.edu.

Background—Desensitization of the cyclic adenosine monophosphate signal protects cardiac myocytes against catecholamine stress, thus preventing the development of apoptosis. Molecular mechanisms of desensitization have been well studied at the level of adrenergic receptors but less so at the level of the effector enzyme, adenylyl cyclase (AC).

Methods and Results—When the effects of long-term (1 to 2 weeks) isoproterenol infusion were compared between type 5 AC-null mice (AC5KO) and wild-type controls, we found that the subsequent responses of left ventricular ejection fraction to sudden intravenous isoproterenol challenge were reduced in AC5KO compared with wild-type mice (ie, physiological desensitization was more effective in AC5KO), consistent with enhanced downregulation of AC catalytic activity in AC5KO. One mechanism for the less effective desensitization in wild-type mice was paradoxical upregulation of type 5 AC protein expression. The number of apoptotic myocytes was similar at baseline but was significantly less in AC5KO after infusion. This was accompanied by a 4-fold greater increase in Bcl-2 and a 3-fold greater increase in phospho-Akt in AC5KO. The latter is most likely mediated by increased membrane localization of phosphoinositide-dependent protein kinase 1, which is known to be inhibited by the cyclic adenosine monophosphate signal.

Conclusions—The absence of type 5 AC results in more effective desensitization after long-term catecholamine stress and protects against the development of myocyte apoptosis and deterioration of cardiac function, potentially elucidating a novel approach to the therapy of heart failure.

Key words: catecholamines • heart failure • apoptosis • signal transduction

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