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

作　　者：Vijay Sharma John H McNeill 

机构地区：[1]Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia [2]BMJ Evidence Centre, BMJ Group, BMA House, Tavistock Square, London, WC1H 9JR, United Kingdom [3]Department of Pathology, Aberdeen Medical School Buildings, Aberdeen Royal Infirmary

出　　处：《World Journal of Cardiology》2011年第9期281-302,共22页世界心脏病学杂志（英文版）（电子版）

基　　金：Supported by The Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada

摘　　要：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 β-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 β-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 benefi cial effects are more likely to be due to prosurvival effects of chronic treatment. These studies have expanded our understanding of the range of effects produced by β-adrenergic blockade and showhow 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 fi rst was upstream stimulatory factor-2-mediated repression of transcriptional master regulator PGC-1α, most likely occurring as a consequence of the improved function; it is unclear whether this effect is unique to β-blockers, although repression of carnitine palmitoyltransferase (CPT)-1 has not been reported with other drugs which improve function. The second was the identif ication of a range of covalent modifications which can regulate CPT-1 directly, mediated by a signalome at the level of the mitochondria. We also identif ied an important interaction between β-adrenergic signaling and caveolins, which may be a key mechanism of action of β-adrenergic blockade. Our experience with this labyrinthine signaling web illustrates that initial hypotheses and anticipat-ed directions do not have to be right in order to open up meaningful directions or reveal new inforDiabetic 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 β-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 β-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 β-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-1α, most likely occurring as a consequence of the improved function; it is unclear whether this effect is unique to β-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 β-adrenergic signaling and caveolins, which may be a key mechanism of action of β-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 informat

关 键 词：Diabetes Heart failure Β-BLOCKERS CARDIAC metabolism FATTY acid oxidation 

分 类 号：R587.2[医药卫生—内分泌]