Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions.
We assessed 1) whether pretreatment before ischemia with pioglitazone (Pio) limits infarct size (IS) and whether this protective effect is due to nitric oxide synthase (NOS) and/or prostaglandin production, as has been shown for atorvastatin (ATV); and 2) whether Pio and ATV have synergistic effects on myocardial protection. Sprague-Dawley rats received oral ATV (10 mg.kg-1.day-1), Pio (10 mg.kg-1.day-1), their combination (Pio+ATV), or water alone for 3 days. Additional rats received Pio (10 mg.kg-1.day-1) for 3 days and intravenous SC-58125 [a cyclooxygenase-2 (COX-2) inhibitor] or SC-560 (a COX-1 inhibitor) 15 min before ischemia. Rats underwent 30 min of myocardial ischemia and 4 h of reperfusion, or hearts were harvested for analysis. IS in the Pio and in the ATV groups was significantly smaller than in the sham-treated group. IS in the Pio+ATV group was smaller than in all other groups (P<0.001 vs. each group). The protective effect of Pio was abrogated by SC-58125 but not by SC-560. Pio, ATV, and Pio + ATV increased the expression and activity of cytosolic phospholipase A2 (cPLA2) and COX-2. ATV increased phosphorylated-Akt, phosphorylated-endothelial NOS (P-eNOS), inducible NOS, and COX-2 levels. In contrast, Pio caused an insignificant increase in myocardial levels of phosphorylated-Akt but did not change P-eNOS and iNOS expression. In conclusion, the IS-limiting effects of Pio and ATV involve COX-2. However, the upstream steps differ. ATV induced eNOS phosphorylation and iNOS, cPLA2, and COX-2 expression, whereas Pio induced mainly the expression and activity of cPLA2. The effects of Pio and ATV were additive.
Ye
Yumei
Y
Division of Cardiology, Department of Biochemistry and Molecular Genetics, University of Texas Medical Branch, 5.106 John Sealy Annex, 301 Univ. Blvd., Galveston, Texas 77555-0553, USA.
Lin
Yu
Y
Atar
Shaul
S
Huang
Ming-He
MH
Perez-Polo
Jose R
JR
Uretsky
Barry F
BF
Birnbaum
Yochai
Y
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000069059:Atorvastatin; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000072181:Inositol Polyphosphate 5-Phosphatases; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010741:Phospholipases A / Q000235:genetics / Q000378:metabolism; D054467:Phospholipases A2; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D000077205:Pioglitazone; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D016861:Cyclooxygenase Inhibitors; D006538:Heptanoic Acids; D007004:Hypoglycemic Agents; D011720:Pyrazoles; D011758:Pyrroles; D045162:Thiazolidinediones; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; D051546:Cyclooxygenase 2; D051058:Oncogene Protein v-akt; D010741:Phospholipases A; D054467:Phospholipases A2; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; D000077205:Pioglitazone