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 ⅐ kg Ϫ1 ⅐ day Ϫ1 ), Pio (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), their combination (Pio ϩ ATV), or water alone for 3 days. Additional rats received Pio (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) 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 ϩ ATV group was smaller than in all other groups (P Ͻ 0.001 vs. each group). The protective effect of Pio was abrogated by SC-58125 but not by SC-560. Pio, ATV, and Pio ϩ ATV increased the expression and activity of cytosolic phospholipase A 2 (cPLA2) and COX-2. ATV increased phosphorylatedAkt, 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, cPLA 2, and COX-2 expression, whereas Pio induced mainly the expression and activity of cPLA 2. The effects of Pio and ATV were additive. infarct size; thiazolidinediones; statins; cyclooxygenase-2; cytosolic phospholipase A2; nitric oxide synthase; protein kinase Akt; phosphatase and tensin homologue deleted on chromosome 10, anti-Src homology 2-containing inositol phosphatase-2

Pioglitazone attenuates myocardial ischemia-reperfusion injury via up-regulation of ERK and COX-2

“…Nevertheless, there are conflicting reports regarding the effect of TZDs on Akt phosphorylation. In another study, PIO caused a minor, but insignificant increase in myocardial P-Akt expression (14). This suggests that the IS-limiting effect of PIO is probably independent of Akt phosphorylation.…”

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

“…The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to decrease cardiovascular morbidity and mortality when administered before elective surgery or percutaneous coronary interventions (39), and recently, the American College of Cardiology/American Heart Association guidelines gave class IIa recommendation for the initiation of statin therapy before vascular surgery and class IIb recommendation for the initiation of statin therapy in patients with risk factors scheduled for intermediate risk surgery (21). Animal studies have shown that statins protect against ischemia-reperfusion injury and when administered before ischemia (2,5,7,31,32,46,48,49,54,55,59,62,63,68,69), or immediately upon reperfusion (4, 18, 62), limit myocardial infarct size (IS). The activation of eNOS is essential for the IS-limiting effects of late ischemic preconditioning (8,9,53,66).…”

“…Thiazolidinediones, a class of drugs with peroxisome proliferator-activated receptor-␥ (PPAR␥) agonist activity, have been shown to reduce myocardial IS in the rat (29,58,60,69,73,74). In a study that compared the IS-limiting effects of atorvastatin and Pio in the rat, our group has found that a 3-day pretreatment with oral Pio at 10 mg⅐kg Ϫ1 ⅐day Ϫ1 limited IS and caused an insignificant increase in myocardial levels of phosphorylated (p)-Akt, without a detectable change in Ser1177 p-eNOS, and -iNOS levels (69).…”

“…In a study that compared the IS-limiting effects of atorvastatin and Pio in the rat, our group has found that a 3-day pretreatment with oral Pio at 10 mg⅐kg Ϫ1 ⅐day Ϫ1 limited IS and caused an insignificant increase in myocardial levels of phosphorylated (p)-Akt, without a detectable change in Ser1177 p-eNOS, and -iNOS levels (69). In contrast, atorvastatin (10 mg⅐kg Ϫ1 ⅐day Ϫ1 ) caused a significant increase in myocardial p-Akt, Ser1177 p-eNOS and -iNOS levels (69). Both atorvastatin and Pio upregulated cytosolic phospholipase A 2 (cPLA 2 ) and cyclooxygenase-2 (COX2) expression and activity, and the IS-limiting effects of both agents were abrogated with COX2 inhibitors (69).…”

“…In contrast, atorvastatin (10 mg⅐kg Ϫ1 ⅐day Ϫ1 ) caused a significant increase in myocardial p-Akt, Ser1177 p-eNOS and -iNOS levels (69). Both atorvastatin and Pio upregulated cytosolic phospholipase A 2 (cPLA 2 ) and cyclooxygenase-2 (COX2) expression and activity, and the IS-limiting effects of both agents were abrogated with COX2 inhibitors (69). Thus it seems that statins and Pio activate cPLA 2 and COX2 by different mechanisms.…”