Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 290, Issue 5, Pages H1899-H1904Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.01014.2005
Keywords
cardiac; left ventricular dysfunction; ceramide; triglycerides; fatty acids
Funding
- NHLBI NIH HHS [HL-74237, HL-074259] Funding Source: Medline
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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-alpha (PPAR alpha) increases intramyocellular ceramide and left ventricular (LV) dysfunction. We tested the hypothesis that activation of fatty acid metabolism with fat feeding or a PPAR alpha 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 alpha 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 alpha agonist resulted in LV hypertrophy (24% increase in LV/body mass ratio) and induced mRNAs encoding for PPAR alpha-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.
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