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

Abstract

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 (PPARalpha) increases intramyocellular ceramide and left ventricular (LV) dysfunction. We tested the hypothesis that activation of fatty acid metabolism with fat feeding or a PPARalpha 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 PPARalpha 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 PPARalpha agonist resulted in LV hypertrophy (24% increase in LV/body mass ratio) and induced mRNAs encoding for PPARalpha-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.

Peroxisome proliferator-activated receptor- reduces inflammation and vascular leakage in a murine model of acute lung injury

“…The current authors speculate that WY protected the lungs from PAF-induced permeability due inhibition of the PGE 2 (COX-1) or ceramide (ASM) pathway [36]. Evidence is accumulating that activation of PPAR-a induces an increase in ceramides, although these data were generated in hearts and not in lungs [37,38]. Taking this together with the reduction in PGE 2 as determined in the BAL after LPS challenge in vivo, the COX-1 and COX-2 pathways can be considered primary targets of PPAR-a in effects on permeability in the present model.…”

Peroxisome Proliferator-activated Receptor (PPAR) Gene Profiling Uncovers Insulin-like Growth Factor-1 as a PPARα Target Gene in Cardioprotection

“…However, reactivation of PPAR␣ by a selective agonist in the heart in different models of heart failure has yielded diverse effects. Rats treated with a PPAR␣ agonist and subjected to pressure overload-induced hypertrophy developed contractile dysfunction (40), whereas a rat model of postinfarction heart failure showed enhanced LV hypertrophy but with no apparent deterioration of cardiac function (41). These results indicate that the different etiologies of heart failure respond differently on PPAR␣ activation, probably due to diverse regulation of cardiac substrate metabolism.…”

The myocardial contractile response to physiological stress improves with high saturated fat feeding in heart failure

“…Other studies have reported that neither a high saturated or polyunsaturated fat diet altered cardiac mass or adversely affected cardiac function. A diet high in lard (a mix of saturated and unsaturated fat) did not further compromise cardiac function after infarction-induced HF (27), whereas a high saturated fat diet prevented HF and death associated with chronic hypertension (28,40,44). Interestingly, it may be the carbohydrate composition of a diet, and not fats, that have the greater impact based on evidence linking increased glycemic load to greater cardiovascular risk (8), a concept that demands further investigation.…”