Altered beta-adrenergic receptor gene regulation and signaling in chronic heart failure

Beta adrenergic receptors (beta -ARs) are critical regulators of cardiac Fu nction in both normal and pathophysiological states. Under normal condition s, beta -ARs and their signaling pathways modulate both the rate and force of myocardial contraction and relaxation. allowing individuals to respond a ppropriately to physiological stress or exercise, However, in chronic heart failure. sustained activation of the beta -AR signaling pathways can have overtly negative biological consequences. This notion is reinforced by the positive outcomes of a number of clinical trials demonstrating the usefulne ss of betablocker therapy in chronic congestive heart failure. During the l ast few years, significant progress has been made in understanding the mole cular biological basis of beta -AR Function, both at the biochemical and ge netic levels. In this review, the biological basis of adrenergic signaling and how this changes in heart failure is discussed. Aspects of adrenergic r eceptor pharmacology relevant to heart failure are reviewed, including the recently emerging differences described for beta (1)- v beta (2)-AR signali ng pathways. Highlighting these differences is recent evidence that over-st imulation of the beta (1)-AR pathway in cardiac myocytes appears to be pro- apoptotic. whereas stimulation of the beta (2)-AR pathway may be anti-apopt otic. Overview of beta -AR gene regulation, transgenic models of beta -AR o verexpression. and beta -AR polymorphisms as they relate to heart failure p rogression are also discussed. (C) 2001 Academic Press.