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1 Physiology & Biophysics, Case Western Reserve University, Cleveland, Ohio, United States
2 Case Western Reserve University, United States
3 Pharmacology, Case Western Reserve University, Cleveland, Ohio, United States
4 Medicine, Case Western Reserve University, Cleveland, Ohio, United States; University Hospitals of Cleveland, Cleveland, Ohio, United States
5 Nutrition, Louis Stokes VA Medical Center, Cleveland, Ohio, United States
6 Pharmacology and Medicine, Case Western Reserve University, Cleveland, Ohio, United States; Nutrition, Louis Stokes VA Medical Center, Cleveland, Ohio, United States
7 Dept. of Physiology & Biophysics - Medical School, Case Western Reserve University, Cleveland, Ohio, United States
* To whom correspondence should be addressed. E-mail: mpc10{at}case.edu.
Lipid accumulation in non-adipose tissue due to enhanced circulating fatty acids may play a role in the pathophysiology of heart failure, obesity, and diabetes. Accumulation of myocardial lipids and related intermediates, e.g., ceramide, is associated with decreased contractile function, mitochondrial oxidative phosphorylation, and electron transport chain complex activities. We tested the hypothesis that the progression of heart failure would be exacerbated by elevated myocardial lipids and an associated ceramide-induced inhibition of mitochondrial oxidative phosphorylation and electron transport chain complex (ETC) activities. Heart failure was induced by coronary artery ligation. Rats were then randomly assigned to either a normal (10% kcal from fat; HF, n=8) or high saturated fat diet (60% kcal from saturated fat) (HF+SAT, n=7). Sham-operated animals (n=8) were fed a normal diet. Eight weeks post ligation, left ventricular (LV) function was assessed by echocardiography and catheterization. Subsarcolemmal and interfibrillar mitochondria were isolated from the LV. Heart failure resulted in impaired LV contractile function (decreased percent fractional shortening and peak LV +/- dP/dt) and remodeling (increased end-diastolic and end-systolic dimensions) in HF compared to SHAM. No further progression of LV dysfunction was evident in HF+SAT. Mitochondrial state 3 respiration was increased in HF+SAT compared to HF despite elevated myocardial ceramide. Activities of electron transport chain complexes II and IV were elevated in HF+SAT compared to HF and SHAM. High saturated fat feeding following coronary artery ligation was associated with increased mitochondrial oxidative phosphorylation and ETC complex activities and did not adversely affect LV contractile function or remodeling, despite elevations in myocardial ceramide.
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