title: Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Ye
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.forename: Shaul
authors.initials: S
authors.lastname: Atar
authors.forename: Ming-He
authors.initials: MH
authors.lastname: Huang
authors.forename: Jose R
authors.initials: JR
authors.lastname: Perez-Polo
authors.forename: Barry F
authors.initials: BF
authors.lastname: Uretsky
authors.forename: Yochai
authors.initials: Y
authors.lastname: Birnbaum
mesh_terms: 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*
chemical_list: 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