Activation of peroxisome proliferator-activated receptor-alpha protects the heart from ischemia/reperfusion injury.
BACKGROUND
Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is expressed in the heart and regulates genes involved in myocardial fatty acid oxidation (FAO). The role of PPAR-alpha in acute ischemia/reperfusion myocardial injury remains unclear.


RESULTS
The coronary arteries of male mice were ligated for 30 minutes. After reperfusion for 24 hours, ischemic and infarct sizes were determined. A highly selective and potent PPAR-alpha agonist, GW7647, was administered by mouth for 2 days, and the third dose was given 1 hour before ischemia. GW7647 at 1 and 3 mg x kg(-1) x d(-1) reduced infarct size by 28% and 35%, respectively (P<0.01), and myocardial contractile dysfunction was also improved. Cardioprotection by GW7647 was completely abolished in PPAR-alpha-null mice. Ischemia/reperfusion downregulated mRNA expression of cardiac PPAR-alpha and FAO enzyme genes, decreased myocardial FAO enzyme activity and in vivo cardiac fat oxidation, and increased serum levels of free fatty acids. All of these changes were reversed by GW7647. Moreover, GW7647 attenuated ischemia/reperfusion-induced release of multiple proinflammatory cytokines and inhibited neutrophil accumulation and myocardial expression of matrix metalloproteinases-9 and -2. Furthermore, GW7647 inhibited nuclear factor-kappaB activation in the heart, accompanied by enhanced levels of inhibitor-kappaBalpha.


CONCLUSIONS
Activation of PPAR-alpha protected the heart from reperfusion injury. This cardioprotection might be mediated through metabolic and antiinflammatory mechanisms. This novel effect of the PPAR-alpha agonist could provide an added benefit to patients treated with PPAR-alpha activators for dyslipidemia.
Yue
Tian-li
TL
GlaxoSmithKline Pharmaceuticals, King of Prussia, 709 Swedeland Rd, King of Prussia, Pa 19406, USA. tian-li_yue@gsk.com
Bao
Weike
W
Jucker
Beat M
BM
Gu
Juan-li
JL
Romanic
Anne M
AM
Brown
Peter J
PJ
Cui
Jianqi
J
Thudium
Douglas T
DT
Boyce
Rogely
R
Burns-Kurtis
Cynthia L
CL
Mirabile
Rosanna C
RC
Aravindhan
Karpagam
K
Ohlstein
Eliot H
EH
D000818:Animals; D002087:Butyrates / Q000008:administration & dosage / Q000627:therapeutic use*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005227:Fatty Acids / Q000097:blood; D020672:I-kappa B Proteins / Q000096:biosynthesis; D008026:Ligation; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D011292:Premedication; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D002087:Butyrates; D016207:Cytokines; D005227:Fatty Acids; C453899:GW 7647; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha; D020782:Matrix Metalloproteinases