Modulation of β-adrenergic receptor signaling in heart failure and longevity: Targeting adenylyl cyclase type 5

David Ho, Lin Yan, Kousaku Iwatsubo, Dorothy E. Vatner, Stephen F. Vatner

Research output: Contribution to journalReview articlepeer-review

41 Scopus citations

Abstract

Despite remarkable advances in therapy, heart failure remains a leading cause of morbidity and mortality. Although enhanced β-adrenergic receptor stimulation is part of normal physiologic adaptation to either the increase in physiologic demand or decrease in cardiac function, chronic β-adrenergic stimulation has been associated with increased mortality and morbidity in both animal models and humans. For example, overexpression of cardiac Gsα or β-adrenergic receptors in transgenic mice results in enhanced cardiac function in young animals, but with prolonged overstimulation of this pathway, cardiomyopathy develops in these mice as they age. Similarly, chronic sympathomimetic amine therapy increases morbidity and mortality in patients with heart failure. Conversely, the use of β-blockade has proven to be of benefit and is currently part of the standard of care for heart failure. It is conceivable that interrupting distal mechanisms in the β-adrenergic receptor-G protein-adenylyl cyclase pathway may also provide targets for future therapeutic modalities for heart failure. Interestingly, there are two major isoforms of adenylyl cyclase (AC) in the heart (type 5 and type 6), which may exert opposite effects on the heart, i.e., cardiac overexpression of AC6 appears to be protective, whereas disruption of type 5 AC prolongs longevity and protects against cardiac stress. The goal of this review is to summarize the paradigm shift in the treatment of heart failure over the past 50 years from administering sympathomimetic amine agonists to administering β-adrenergic receptor antagonists, and to explore the basis for a novel therapy of inhibiting type 5 AC.

Original languageEnglish (US)
Pages (from-to)495-512
Number of pages18
JournalHeart Failure Reviews
Volume15
Issue number5
DOIs
StatePublished - Sep 2010

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Keywords

  • Adenylyl cyclase
  • Heart failure
  • Longevity
  • β-Adrenergic receptors

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