A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content.
To explore the role of peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated derangements in myocardial metabolism in the pathogenesis of diabetic cardiomyopathy, insulinopenic mice with PPARalpha deficiency (PPARalpha(-/-)) or cardiac-restricted overexpression [myosin heavy chain (MHC)-PPAR] were characterized. Whereas PPARalpha(-/-) mice were protected from the development of diabetes-induced cardiac hypertrophy, the combination of diabetes and the MHC-PPAR genotype resulted in a more severe cardiomyopathic phenotype than either did alone. Cardiomyopathy in diabetic MHC-PPAR mice was accompanied by myocardial long-chain triglyceride accumulation. The cardiomyopathic phenotype was exacerbated in MHC-PPAR mice fed a diet enriched in triglyceride containing long-chain fatty acid, an effect that was reversed by discontinuing the high-fat diet and absent in mice given a medium-chain triglyceride-enriched diet. Reactive oxygen intermediates were identified as candidate mediators of cardiomyopathic effects in MHC-PPAR mice. These results link dysregulation of the PPARalpha gene regulatory pathway to cardiac dysfunction in the diabetic and provide a rationale for serum lipid-lowering strategies in the treatment of diabetic cardiomyopathy.
Finck
Brian N
BN
Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Han
Xianlin
X
Courtois
Michael
M
Aimond
Franck
F
Nerbonne
Jeanne M
JM
Kovacs
Attila
A
Gross
Richard W
RW
Kelly
Daniel P
DP
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D002518:Ceramides / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000473:pathology; D004041:Dietary Fats / Q000494:pharmacology; D004452:Echocardiography; D004594:Electrophysiology; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D050356:Lipid Metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism
D002518:Ceramides; D004041:Dietary Fats; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D005978:Glutathione