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Reactivation of Peroxisome Proliferator-Activated Receptor Alpha in Spontaneously Hypertensive Rat: Age Associated Paradoxical Effect on the Heart.
MedLine Citation:
PMID:  21654328     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 (FAO) enzyme genes. Though initially adaptive, the metabolic switch appears to be detrimental in the long run. This study was taken up with the objective of examining whether stimulation of FAO by 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 rat (SHR) in the initial stages of hypertrophy (2 months) and those with established hypertrophy (6 months) were treated with fenofibrate (100mg/kg/day for 60 days). Cluster of differentiation 36 (CD36) - responsible for myocardial fatty acid uptake, carnitine palmitoyl transferase 1β (CPT 1β) - a mitochondrial transporter protein and medium chain acyl-Co-A dehydrogenase (MCAD) - 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 SHR. 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 CPT 1β and MCAD were upregulated on treatment. However, CD36 showed an age dependent variation upon treatment, with no change in expression in young rats and downregulation in older animals. It is inferred that stimulation of PPARα before the initiation of metabolic remodeling may prevent cardiac hypertrophy; but reactivation after the metabolic adaptation aggravates hypertrophy. Whether 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:
Sreeja Purushothaman; M B Mohamed Sathik; R Renuka Nair
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-6-03
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  -     ISSN:  1533-4023     ISO Abbreviation:  -     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-6-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum- 695 011, India; 2Molecular Plant Physiology, Crop Physiology Division, Rubber Research Institute of India, Rubber Board, Kottayam 686 009, India.
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