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Title: Enhanced acyl-CoA dehydrogenase activity is associated with improved mitochondrial and contractile function in heart failure

item Rennison, Julie
item Mcelfresh, Tracy
item Okere, Isidore
item Patel, Hiral
item Foster, Amy
item Patel, Kalpana
item Stoll, Maria
item Minkler, Paul
item Fujioka, Hisashi
item Hoit, Brian
item Young, Martin
item Hoppel, Charles
item Chandler, Margaret

Submitted to: Cardiovascular Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/5/2008
Publication Date: 3/13/2008
Citation: Rennison, J.H., McElfresh, T.A., Okere, I.C., Patel, H.V., Foster, A.B., Patel, K.K., Stoll, M.S., Minkler, P.E., Fujioka, H., Hoit, B.D., Young, M.E., Hoppel, C.L., Chandler, M.P. 2008. Enhanced acyl-CoA dehydrogenase activity is associated with improved mitochondrial and contractile function in heart failure. Cardiovascular Research. 79(2):331-340.

Interpretive Summary: An inability of the heart to pump enough blood is termed heart failure. One possible explanation for heart failure is that the heart is not able to generate enough energy. Problems with fatty acid metabolism have been suggested as a possible factor in decreased energy. This study investigated whether providing more fatty acids in the diet would improve heart function, and the ability of the heart to generate energy from fatty acids, during heart failure. The study found that increasing fatty acids in the diet slightly improved heart function, and the ability of the heart to use fatty acids as a fuel. These data are consistent with the idea that defective energy metabolism contributes toward heart disease.

Technical Abstract: 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. 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. 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 with 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. 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.