Antidiabetic drug pioglitazone protects the heart via activation of PPAR-gamma receptors, PI3-kinase, Akt, and eNOS pathway in a rabbit model of myocardial infarction.
The insulin-sensitizing drug pioglitazone has been reported to be protective against myocardial infarction. However, its precise mechanism is unclear. Rabbits underwent 30 min of coronary occlusion followed by 48 h of reperfusion. Rabbits were assigned randomly to nine groups (n = 10 in each): the control group (fed a normal diet), pioglitazone group (fed diets containing 1 mg.kg(-1).day(-1) pioglitazone), pioglitazone + 5-hydroxydecanoic acid (HD) group [fed the pioglitazone diet + 5 mg/kg iv 5-HD, a mitochondrial ATP-sensitive K(+) (K(ATP)) channel blocker], pioglitazone + GW9662 group [fed the pioglitazone diet + 2 mg/kg iv GW9662, a peroxisome proliferator activated receptor (PPAR)-gamma antagonist], GW9662 group (fed a normal diet + iv GW9662), pioglitazone + wortmannin group [fed the pioglitazone diet + 0.6 mg/kg iv wortmannin, a phosphatidylinositol (PI)3-kinase inhibitor], wortmannin group (fed a normal diet + iv wortmannin), pioglitazone + nitro-l-arginine methyl ester (l-NAME) group [fed the pioglitazone diet + 10 mg/kg iv l-NAME, a nitric oxide synthase (NOS) inhibitor], and l-NAME group (fed a normal diet + iv l-NAME). All groups were fed the diets for 7 days. The risk area and nonrisk area of the left ventricle (LV) were separated by Evans blue dye, and the infarct area was determined by triphenyltetrazolium chloride staining. The infarct size was calculated as a percentage of the LV risk area. Western blotting was performed to assess levels of Akt and phospho-Akt and phospho-endothelial NOS (eNOS) in the myocardium following reperfusion. The infarct size was significantly smaller in the pioglitazone group (21 +/- 2%) than in the control group (43 +/- 3%). This effect was abolished by GW9662 (42 +/- 3%), wortmannin (40 +/- 3%), or l-NAME (42 +/- 7%) but not by 5-HD (24 +/- 5%). Western blotting showed higher levels of phospho-Akt and phospho-eNOS in the pioglitazone group. Pioglitazone reduces the myocardial infarct size via activation of PPAR-gamma, PI3-kinase, Akt, and eNOS pathways, but not via opening the mitochondrial K(ATP) channel. Pioglitazone may be a novel strategy for the treatment of diabetes mellitus with coronary artery disease.
Yasuda
Shinji
S
Dept. of Cardiology, Gifu Univ. Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Kobayashi
Hiroyuki
H
Iwasa
Masamitsu
M
Kawamura
Itta
I
Sumi
Shouhei
S
Narentuoya
Bao
B
Yamaki
Takahiko
T
Ushikoshi
Hiroaki
H
Nishigaki
Kazuhiko
K
Nagashima
Kenshi
K
Takemura
Genzou
G
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
Minatoguchi
Shinya
S
D000730:Androstadienes / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D015153:Blotting, Western; D003652:Decanoic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006439:Hemodynamics / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D000077205:Pioglitazone; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011817:Rabbits; D045162:Thiazolidinediones / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D000077191:Wortmannin
C457499:2-chloro-5-nitrobenzanilide; D000730:Androstadienes; D000813:Anilides; D001786:Blood Glucose; D003652:Decanoic Acids; D006880:Hydroxy Acids; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; D045162:Thiazolidinediones; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019331:NG-Nitroarginine Methyl Ester; D000077205:Pioglitazone; D000077191:Wortmannin