Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 13, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn066
Enhanced Acyl-CoA Dehydrogenase Activity is Associated with Improved Mitochondrial and Contractile Function in Heart Failure
1 Departments of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH
2 Pharmacology, Case Western Reserve University, Cleveland, OH
3 Medicine, Case Western Reserve University, Cleveland, OH
4 University Hospitals Case Medical Center, Cleveland, OH
5 Baylor College of Medicine, Houston, TX
Address for correspondence: Margaret P. Chandler, Ph.D. Department of Physiology and Biophysics School of Medicine E553, Case Western Reserve University, 10900 Euclid Avenue,Cleveland, OH 44106-4970 216-368-3367 (Phone) 216-368-3952 (FAX) e-mail: mpc10{at}case.edu
Aims: Heart failure is associated with decreased myocardial fatty acid oxidation capacity and has been likened to energy starvation. Increased fatty acid availability results in an induction of genes promoting fatty acid oxidation. The aim of the present study was to investigate possible mechanisms by which high fat feeding improved mitochondrial and contractile function in heart failure.
Methods: Male Wistar rats underwent coronary artery ligation (HF) or sham surgery and were immediately fed either a normal (14% kcal fat) (SHAM, HF) or high fat diet (60% kcal saturated fat) (SHAM+FAT, HF+FAT) for 8 weeks. Mitochondrial respiration and gene expression and enzyme activities of fatty acid-regulated mitochondrial genes and proteins were assessed.
Results: Subsarcolemmal (SSM) and interfibrillar mitochondria were isolated from the left ventricle. State 3 respiration using lipid substrates octanoylcarnitine and palmitoylcarnitine increased in the SSM of HF+FAT compared to SHAM+FAT and HF, respectively (242±21, 246±21 vs 183±8, 181±6 and 193±17, 185±16 nAO·min–1·mg–1). Despite decreased medium-chain acyl-CoA dehydrogenase (MCAD) mRNA in HF and HF+FAT, MCAD protein was not altered, and MCAD activity increased in HF+FAT (HF, 65.1±2.7 vs HF+FAT, 81.5±5.4 nmoles·min–1·mg–1). Activities of short- and long-chain acyl-CoA dehydrogenase also were elevated and correlated to increased state 3 respiration. This was associated with an improvement in myocardial contractility as assessed by left ventricular +dP/dt max.
Conclusions: Administration of a high fat diet increased state 3 respiration and acyl-CoA dehydrogenase activities, but did not normalize mRNA or protein levels of acyl-CoA dehydrogenases in coronary artery ligation-induced heart failure rats.
Time for primary review: 31 days
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