title: 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.
authors.affiliation: Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India.
authors.forename: Sreeja
authors.initials: S
authors.lastname: Purushothaman
authors.forename: Mb Mohamed
authors.initials: MM
authors.lastname: Sathik
authors.forename: R Renuka
authors.initials: RR
authors.lastname: Nair
mesh_terms: D000375:Aging; D000818:Animals; D001391:Azo Compounds; D001794:Blood Pressure; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use*; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000960:Hypolipidemic Agents / Q000378:metabolism / Q000494:pharmacology; D015227:Lipid Peroxidation; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013997:Time Factors; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D001391:Azo Compounds; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D002784:Cholesterol; C011049:oil red O; D011345:Fenofibrate