Effect of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on ischemia-reperfusion injury in rats.
Two groups of rats were used to examine the effect of pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, on rat hearts using an in vivo model of ischemia-reperfusion (I/R) to elucidate potential mechanisms. One group was the 30-min reperfusion group, which was further subdivided into sham (n=5), vehicle (n=6) and pioglitazone (3 mg x kg(-1), n=7) treatment groups with 30 min ischemia followed by 30 min reperfusion to detect data related to cardiac function and the area of myocardial infarction. The other group was the 120-min reperfusion group, subdivided into sham (n=5), vehicle (n=6), and pioglitazone 0.3 mg x kg(-1) (n=6), 1 mg x kg(-1) (n=7) and 3 mg x kg(-1) (n=6) treatment groups. Immunohistochemistry, in situ hybridization, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) and DNA agarose gel electrophoresis were performed to detect apoptosis and expressions of Bax, Bcl-2, caspase 3, MMP-2 and PPARgamma protein, and MMP-2 and PPARgamma mRNA. We found that, after acute treatment with pioglitazone, the ratio of necrosis to area at risk decreased by 28% (p<0.01) and that of necrosis to left ventricle was reduced by 32% (p<0.01), compared with the vehicle group. Heart rate and +dp/dt(max), representing the cardiac systolic function, as well as -dp/dt(max), the indicator of cardiac diastolic function, improved significantly at 1 and 30 min after reperfusion (p<0.05-0.01). Furthermore, myocardial apoptosis was significantly suppressed by acute treatment with pioglitazone as evidenced by the decreased number of TUNEL-positive myocytes and DNA ladder, enhanced Bcl-2 protein expression, reduced Bax and caspase 3 protein expression in a dose-dependent manner compared with vehicle-treated rats. In addition, acute treatment with pioglitazone dose-dependently increased PPARgamma expression and decreased MMP-2 expression at protein and mRNA levels. Our findings demonstrate that a PPARgamma agonist may protect the heart from I/R injury. The protective effect is likely to occur by reducing cardiomyocyte apoptosis and inhibiting MMP-2.
Cao
Zeling
Z
Department of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, People's Republic of China.
Ye
Ping
P
Long
Chaoliang
C
Chen
Kai
K
Li
Xiaowei
X
Wang
Hai
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004587:Electrophoresis, Agar Gel; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling / Q000379:methods; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism
C494828:Bax protein, rat; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D045162:Thiazolidinediones; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; D000077205:Pioglitazone