Downregulation of peroxisome proliferator-activated receptor-alpha gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity.
BACKGROUND
The peroxisome proliferators-activated receptor-alpha (PPARalpha), a transcription factor that modulates fatty acid metabolism, regulates substrate preference in the heart. Although in acute ischemia there is a switch in substrate preference from fatty acids to glucose, metabolic gene expression in repetitive ischemia is not well described. In a mouse model of ischemic cardiomyopathy induced by repetitive ischemia/reperfusion (I/R), we postulated that downregulation of PPARalpha is regulated by reactive oxygen species and is necessary for maintaining contractile function in the heart.


RESULTS
Repetitive closed-chest I/R (15 minutes) was performed daily in C57/BL6 mice, mice overexpressing extracellular superoxide dismutase, and mice treated with the PPARalpha agonist-WY-14,643. Echocardiography, histology, and candidate gene expression were measured at 3, 5, 7, and 28 days of repetitive I/R and 15 and 30 days after discontinuation of I/R. Repetitive I/R was associated with a downregulation of PPARalpha-regulated genes and both myosin heavy chain isoform transcript levels, which was reversible on discontinuation of I/R. Overexpression of EC-SOD prevented the downregulation of PPARalpha-regulated genes and myosin iso-genes by repetitive I/R. Furthermore, reactivation of PPARalpha in mice exposed to repetitive I/R worsened contractile function, induced microinfarctions, and increased intramyocardial triglyceride deposition, features suggestive of cardiac lipotoxicity.


CONCLUSIONS
Metabolic and myosin isoform gene expression in repetitive I/R is mediated by reactive oxygen species. Furthermore, we suggest that downregulation of PPARalpha in repetitive I/R is an adaptive mechanism that is able to prevent lipotoxicity in the ischemic myocardium.
Dewald
Oliver
O
Division of Cardiology, Department of Internal Medicine, University of Texas Houston Medical School, 6431 Fannin St, MSB 1.246, Houston, TX 77030, USA.
Sharma
Saumya
S
Adrogue
Julia
J
Salazar
Rebecca
R
Duerr
Georg D
GD
Crapo
James D
JD
Entman
Mark L
ML
Taegtmeyer
Heinrich
H
D000818:Animals; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000378:metabolism*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D047493:PPAR alpha / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism / Q000633:toxicity*
D005227:Fatty Acids; D047493:PPAR alpha; D017382:Reactive Oxygen Species; D014280:Triglycerides; D013482:Superoxide Dismutase; D018995:Myosin Heavy Chains