Beta-adrenergic receptor-G protein-adenylyl cyclase signal transduction in the failing heart.

Abstract

The beta-adrenergic receptor signal transduction pathway is critical for rapid adjustments to increased cardiovascular demand (e.g., during exercise). In the face of chronic stimulation of this pathway, as occurs in the pathogenesis of heart failure, beta-adrenergic receptor stimulation may become maladaptive. Under these conditions, elevation of circulating catecholamines and depletion of cardiac tissue stores of norepinephrine occur in the failing heart, resulting in desensitization. Whether or not stimulation or inhibition of the beta-adrenergic receptor signaling pathway is beneficial in heart failure is controversial. One approach to address this question is to specifically overexpress a component of the beta-adrenergic receptor signaling pathway in a transgenic mouse heart. We have characterized young and old adult mice with overexpressed cardiac G(s alpha) which couples the beta-adrenergic receptor to adenylyl cyclase. In younger animals, beta-adrenergic receptor stimulation results in an augmented heart rate and cardiac contractility. Over the life of the animal, however, a picture of cardiomyopathy develops. The result is a dilated heart with a large amount of fibrosis and myocyte hypertrophy, degeneration atrophy, and apoptosis. Conversely, chronic beta-adrenergic receptor blockade prevents the development of cardiomyopathy. These experiments support the point of view that chronic beta-adrenergic stimulation during the development of heart failure is deleterious and that protecting the heart with chronic beta-adrenergic receptor blockade is salutary, conceptually consistent with results of recent clinical trials examining the effects of beta-adrenergic receptor blockers in patients with heart failure.

• Authors: D E Vatner, K Asai, M Iwase, Y Ishikawa, R P Shannon, C J Homcy, S F Vatner
• Journal: The American journal of cardiology (Am J Cardiol) Vol. 83 Issue 12A Pg. 80H-85H (Jun 17 1999) ISSN: 0002-9149 [Print] United States
• PMID: 10750593 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S., Review)

Chemical References

• Adrenergic beta-Agonists
• Catecholamines
• Receptors, Adrenergic, beta
• GTP-Binding Proteins
• Adenylyl Cyclases

Topics

• Adenylyl Cyclases (genetics, metabolism)
• Adrenergic beta-Agonists (pharmacology)
• Animals
• Apoptosis
• Atrophy (metabolism, pathology, prevention & control)
• Catecholamines (metabolism)
• Fibrosis (metabolism, pathology, prevention & control)
• GTP-Binding Proteins (genetics, metabolism)
• Gene Expression (drug effects)
• Heart Failure (drug therapy, metabolism, pathology, physiopathology)
• Humans
• Myocardial Contraction (drug effects)
• Myocardium (metabolism, pathology)
• Receptors, Adrenergic, beta (drug effects, genetics, metabolism)
• Signal Transduction (drug effects, physiology)