Modulation of beta-adrenergic receptor signaling in heart failure and longevity: targeting adenylyl cyclase type 5.

Abstract

Despite remarkable advances in therapy, heart failure remains a leading cause of morbidity and mortality. Although enhanced beta-adrenergic receptor stimulation is part of normal physiologic adaptation to either the increase in physiologic demand or decrease in cardiac function, chronic beta-adrenergic stimulation has been associated with increased mortality and morbidity in both animal models and humans. For example, overexpression of cardiac Gsalpha or beta-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 beta-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 beta-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 beta-adrenergic receptor antagonists, and to explore the basis for a novel therapy of inhibiting type 5 AC.

• Authors: David Ho, Lin Yan, Kousaku Iwatsubo, Dorothy E Vatner, Stephen F Vatner
• Journal: Heart failure reviews (Heart Fail Rev) Vol. 15 Issue 5 Pg. 495-512 (Sep 2010) ISSN: 1573-7322 [Electronic] United States
• PMID: 20658186 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

• Cardiotonic Agents
• Receptors, Adrenergic, beta
• Cyclic AMP
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Adenylyl Cyclases
• adenylyl cyclase type V

Topics

• Adenylyl Cyclases (metabolism)
• Age Factors
• Aging (pathology)
• Apoptosis
• Cardiotonic Agents (therapeutic use)
• Cyclic AMP (metabolism)
• Fibrosis
• Heart Failure (drug therapy, enzymology, physiopathology)
• Humans
• Longevity
• Myocytes, Cardiac (enzymology)
• Receptors, Adrenergic, beta (biosynthesis, physiology)
• Risk Factors
• Sarcoplasmic Reticulum (enzymology)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (metabolism)
• Signal Transduction