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.
| Original language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 291 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2006 |
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Keywords
- Cyclooxygenase-2
- Cytosolic phospholipase A
- Infarct size
- Nitric oxide synthase
- Phosphatase and tensin homologue deleted on chromosome 10, anti-Src homology 2-containing inositol phosphatase-2
- Protein kinase Akt
- Statins
- Thiazolidinediones
ASJC Scopus subject areas
- Physiology
Cite this
Myocardial protection by pioglitazone, atorvastatin, and their combination : Mechanisms and possible interactions. / Ye, Yumei; Lin, Yu; Atar, Shaul; Huang, Ming He; Perez-Polo, Jose R.; Uretsky, Barry F.; Birnbaum, Yochai.
In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 291, No. 3, 2006.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Myocardial protection by pioglitazone, atorvastatin, and their combination
T2 - Mechanisms and possible interactions
AU - Ye, Yumei
AU - Lin, Yu
AU - Atar, Shaul
AU - Huang, Ming He
AU - Perez-Polo, Jose R.
AU - Uretsky, Barry F.
AU - Birnbaum, Yochai
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
KW - Cyclooxygenase-2
KW - Cytosolic phospholipase A
KW - Infarct size
KW - Nitric oxide synthase
KW - Phosphatase and tensin homologue deleted on chromosome 10, anti-Src homology 2-containing inositol phosphatase-2
KW - Protein kinase Akt
KW - Statins
KW - Thiazolidinediones
UR - http://www.scopus.com/inward/record.url?scp=33748368084&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33748368084&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00096.2006
DO - 10.1152/ajpheart.00096.2006
M3 - Article
C2 - 16603698
AN - SCOPUS:33748368084
VL - 291
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
SN - 0193-1849
IS - 3
ER -