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Effects of chronic activation of peroxisome proliferator-activated receptor- or high-fat feeding in a rat infarct model of heart failure

¹Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio; ²Department of Pediatrics, Baylor College of Medicine, Houston, Texas; ³Veteran Affairs Medical Research Center, Cleveland, Ohio; and ⁴Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio

Submitted 23 September 2005 ; accepted in final form 6 December 2005

Intracardiac accumulation of lipid and related intermediates (e.g., ceramide) is associated with cardiac dysfunction and may contribute to the progression of heart failure (HF). Overexpression of nuclear receptor peroxisome proliferator-activated receptor- (PPAR) increases intramyocellular ceramide and left ventricular (LV) dysfunction. We tested the hypothesis that activation of fatty acid metabolism with fat feeding or a PPAR agonist increases myocardial triglyceride and/or ceramide and exacerbates LV dysfunction in HF. Rats with infarct-induced HF (n = 38) or sham-operated rats (n = 10) were either untreated (INF, n = 10), fed a high-fat diet (45% kcal fat, INF + Fat, n = 15), or fed the PPAR agonist fenofibrate (150 mg·kg^–1·day^–1, INF + Feno, n = 13) for 12 wk. LV ejection fraction was significantly reduced with HF (49 ± 6%) compared with sham operated (86 ± 2%) with no significant differences in ejection fraction (or other functional or hemodynamic measures) among the three infarcted groups. Treatment with the PPAR agonist resulted in LV hypertrophy (24% increase in LV/body mass ratio) and induced mRNAs encoding for PPAR-regulated genes, as well as protein expression and activity of medium chain acyl-CoA dehydrogenase (compared with INF and INF + Fat groups). Myocardial ceramide content was elevated in the INF group compared with sham-operated rats, with no further change in the INF + Fat or INF + Feno groups. Myocardial triglyceride was unaffected by infarction but increased in the INF + Fat group. In conclusion, LV dysfunction and dilation are not worsened despite upregulation of the fatty acid metabolic pathway and LV hypertrophy or accumulation of myocardial triglyceride in the rat infarct model of HF.

cardiac; left ventricular dysfunction; ceramide; triglycerides; fatty acids

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