Parallel effects of β-adrenoceptor blockade on cardiac function and fatty acid oxidation in the diabetic heart: Confronting the maze

Diabetic cardiomyopathy is a disease process in which diabetes produces a direct and continuous myocardial insult even in the absence of ischemic, hypertensive or valvular disease. The beta-blocking agents bisoprolol, carvedilol and metoprolol have been shown in large-scale randomized controlled trials to reduce heart failure mortality. In this review, we summarize the results of our studies investigating the effects of beta-blocking agents on cardiac function and metabolism in diabetic heart failure, and the complex inter-related mechanisms involved. Metoprolol inhibits fatty acid oxidation at the mitochondrial level but does not prevent lipotoxicity; its beneficial effects are more likely to be due to pro-survival effects of chronic treatment. These studies have expanded our understanding of the range of effects produced by beta-adrenergic blockade and show how interconnected the signaling pathways of function and metabolism are in the heart. Although our initial hypothesis that inhibition of fatty acid oxidation would be a key mechanism of action was disproved, unexpected results led us to some intriguing regulatory mechanisms of cardiac metabolism. The first was upstream stimulatory factor-2-mediated repression of transcriptional master regulator PGC-1 alpha, most likely occurring as a consequence of the improved function; it is unclear whether this effect is unique to beta-blockers, although repression of carnitine palmitoyltransferase (CPT)-1 has not been reported with other drugs which improve function. The second was the identification of a range of covalent modifications which can regulate CPT-1 directly, mediated by a signalome at the level of the mitochondria. We also identified an important interaction between beta-adrenergic signaling and caveolins, which may be a key mechanism of action of beta-adrenergic blockade. Our experience with this labyrinthine signaling web illustrates that initial hypotheses and anticipated directions do not have to be right in order to open up meaningful directions or reveal new information. (C) 2011 Baishideng. All rights reserved.