Reactivation of Peroxisome Proliferator-activated Receptor Alpha in Spontaneously Hypertensive Rat: Age-associated Paradoxical Effect on the Heart

Abstract

Prevention of left ventricular hypertrophy remains a challenge in the prevention of hypertension-induced adverse cardiac remodeling. Cardiac hypertrophy is associated with a shift in energy metabolism from predominantly fatty acid to glucose with a corresponding reduction in the expression of fatty acid oxidation enzyme genes. Although initially adaptive, the metabolic switch seems to be detrimental in the long run. This study was taken up with the objective of examining whether the stimulation of fatty acid oxidation by the activation of peroxisome proliferator-activated receptor alpha (PPARα), a key regulator of fatty acid metabolism, can prevent cardiac hypertrophy. Fenofibrate was used as the PPARα agonist. Spontaneously hypertensive rats (SHRs) in the initial stages of hypertrophy (2 months) and those with established hypertrophy (6 months) were treated with fenofibrate (100 mg·kg·d for 60 days). Cluster of differentiation 36 (CD36)-responsible for myocardial fatty acid uptake, carnitine palmitoyl transferase 1β-a mitochondrial transporter protein and medium chain acyl-Co-A dehydrogenase-a key enzyme in beta oxidation of fatty acids were selected as indicators of fatty acid metabolism. Hypertrophy was apparent at 2 months and metabolic shift at 4 months of age in SHRs. The treatment prevented cardiac remodeling in young animals but aggravated hypertrophy in older animals. Hypertrophy showed a positive association with malondialdehyde levels and cardiac NF-κB gene expression, signifying the role of oxidative stress in the mediation of hypertrophy. Expression of carnitine palmitoyl transferase 1β and medium chain acyl-Co-A dehydrogenase was upregulated on treatment. However, CD36 showed an age-dependent variation on treatment, with no change in expression in young rats and downregulation in older animals. It is inferred that the stimulation of PPARα before the initiation of metabolic remodeling may prevent cardiac hypertrophy, but reactivation after the metabolic adaptation aggravates hypertrophy. Whether the downregulation of CD36 is mediated by decreased substrate availability remains to be explored. Age-dependent paradoxical effect on the heart in response to fenofibrate, used as a lipid-lowering drug, can have therapeutic implications.

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

“…But these effects are age-dependent. In contrast, when 6-month-old rats are treated with fenofibrate, paradoxical effects are seen — an aggravation of cardiac hypertrophy [68]. As the present study is the first report of cardiac hypertrophy induction in response to fenofibrate, it potentially links the regulation of PPARα (by MuRF1) and induction of cardiac hypertrophy by the transcriptional up-regulation SREBP-1 and E2F.…”

“…Suppression of endothelin-1-induced pathological cardiac hypertrophy by fenofibrate has been shown to involve diacylglycerol (DAG) kinase [59,63], GSK3β [64], ERK1/2, and cJun kinase [65–67]. Fenofibrate's antihypertrophic response is seen in most studies of pathological hypertrophy, including 2-month-old spontaneously hypertensive rats [68]. But these effects are age-dependent.…”

Farnesoid X receptor agonist CDCA reduces blood pressure and regulates vascular tone in spontaneously hypertensive rats

“…44 The PPAR expression and activity have been demonstrated to be diminished in SHR. 45 Whether other molecules to which FXR cross-talked are intact in SHR remains unknown. It is possible that the compensation, cross-talk, and feedback loop mechanisms may be disrupted in SHR.…”

Fenofibrate reduces cardiac remodeling and improves cardiac function in a rat model of severe left ventricle volume overload

“…This dose of fenofibrate was similar to the one used by others in concentric LVH models in the rat (Chen et al 2007;Diep et al 2004;Harvey et al 2011;Iglarz et al 2003;Lebrasseur et al 2007;Purushothaman et al 2011). The treatment was started one week before surgery in both SF and ARF groups and continued for 9 weeks until sacrifice.…”

“…Fibrates are a class of hypolipemic drugs acting on PPARα activation. They have been shown in models of concentric hypertrophy due to pressure overload to have some anti-hypertrophic effects (Chen et al 2007;Diep et al 2004;Harvey et al 2011;Iglarz et al 2003;Lebrasseur et al 2007;Li et al 2009;Nishida et al 2004;Purushothaman et al 2011;Rose et al 2007). …”