Disruption of type 5 adenylyl cyclase enhances desensitization of cyclic adenosine monophosphate signal and increases Akt signal with chronic catecholamine stress

Satoshi Okumura, Dorothy E. Vatner, Reiko Kurotani, Yunzhe Bai, Shumin Gao, Zengrong Yuan, Kousaku Iwatsubo, Coskun Ulucan, Jun Ichi Kawabe, Kaushik Ghosh, Stephen F. Vatner, Yoshihiro Ishikawa

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1776-1783
Number of pages8
JournalCirculation
Volume116
Issue number16
DOIs
StatePublished - Oct 2007

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Keywords

  • Apoptosis
  • Catecholamines
  • Heart failure
  • Signal transduction

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