Adenylyl cyclase type 5 in cardiac disease, metabolism, and aging

Stephen F. Vatner, Misun Park, Lin Yan, Grace J. Lee, Lo Lai, Kousaku Iwatsubo, Yoshihiro Ishikawa, Jeffrey E. Pessin, Dorothy E. Vatner

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

G protein-coupled receptor/adenylyl cyclase (AC)/cAMP signaling is crucial for all cellular responses to physiological and pathophysiological stimuli. There are nine isoforms of membrane-bound AC, with type 5 being one of the two major isoforms in the heart. Since the role of AC in the heart in regulating cAMP and acute changes in inotropic and chronotropic state are well known, this review will address our current understanding of the distinct regulatory role of the AC5 isoform in response to chronic stress. Transgenic overexpression of AC5 in cardiomyocytes of the heart (AC5-Tg) improves baseline cardiac function but impairs the ability of the heart to withstand stress. For example, chronic catecholamine stimulation induces cardiomyopathy, which is more severe in AC5-Tg mice, mediated through the AC5/sirtuin 1/forkhead box O3a pathway. Conversely, disrupting AC5, i.e., AC5 knockout, protects the heart from chronic catecholamine cardiomyopathy as well as the cardiomyopathies resulting from chronic pressure overload or aging. Moreover, AC5 knockout results in a 30% increase in a healthy life span, resembling the most widely studied model of longevity, i.e., calorie restriction. These two models of longevity share similar gene regulation in the heart, muscle, liver, and brain in that they are both protected against diabetes, obesity, and diabetic and aging cardiomyopathy. A pharmacological inhibitor of AC5 also provides protection against cardiac stress, diabetes, and obesity. Thus AC5 inhibition has novel, potential therapeutic applicability to several diseases not only in the heart but also in aging, diabetes, and obesity.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume305
Issue number1
DOIs
StatePublished - Jul 1 2013

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Heart Diseases
Cardiomyopathies
Protein Isoforms
Obesity
Adenylyl Cyclases
Catecholamines
Sirtuin 1
Diabetic Cardiomyopathies
G-Protein-Coupled Receptors
Cardiac Myocytes
adenylyl cyclase type V
Myocardium
Pharmacology
Pressure
Membranes
Liver
Brain
Genes
Therapeutics

Keywords

  • AC5 inhibitor
  • Adenylyl cyclase type 5
  • Aging
  • Cardiomyopathy
  • Metabolism

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Adenylyl cyclase type 5 in cardiac disease, metabolism, and aging. / Vatner, Stephen F.; Park, Misun; Yan, Lin; Lee, Grace J.; Lai, Lo; Iwatsubo, Kousaku; Ishikawa, Yoshihiro; Pessin, Jeffrey E.; Vatner, Dorothy E.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 305, No. 1, 01.07.2013.

Research output: Contribution to journalArticle

Vatner, Stephen F. ; Park, Misun ; Yan, Lin ; Lee, Grace J. ; Lai, Lo ; Iwatsubo, Kousaku ; Ishikawa, Yoshihiro ; Pessin, Jeffrey E. ; Vatner, Dorothy E. / Adenylyl cyclase type 5 in cardiac disease, metabolism, and aging. In: American Journal of Physiology - Heart and Circulatory Physiology. 2013 ; Vol. 305, No. 1.
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