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

Yumei Ye, Yu Lin, Saraswathy Manickavasagam, J. Regino Perez-Polo, Brian C. Tieu, Yochai Birnbaum

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Abstract

Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-γ agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA2 and COX2, and increases myocardial 6-keto-PGF levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS-/- and iNOS-/- mice. Male C57BL/6 wild-type (WT), eNOS-/-, and iNOS-/- mice received 10 mg·kg-1·day-1 Pio (Pio+) or water alone (Pio-) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4 ± 1.4% vs. 39.0 ± 1.1%; P < 0.001), as well as in the eNOS-/- (32.0 ± 1.6% vs. 44.2 ± 1.9%; P < 0.001) and iNOS-/- (18.0 ± 1.2% vs. 45.5 ± 2.3%; P < 0.001) mice. The protective effect of Pio in eNOS-/- mice was smaller than in the WT (P < 0.001) and iNOS -/- (P < 0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS-/- mice. iNOS was undetectable in all six groups. Pio increased cPLA2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS-/- and iNOS-/-, mice. Pio increased the myocardial 6-keto-PGF levels and cPLA2 and COX2 activity in the WT, eNOS-/-, and iNOS-/- mice. In conclusion, the myocardial protective effect of Pio is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume295
Issue number6
DOIs
StatePublished - Dec 2008

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pioglitazone
Nitric Oxide Synthase Type III
Reperfusion Injury
Knockout Mice
Myocardium
Cytosolic Phospholipases A2
Cyclooxygenase 2
Prostaglandins F
Hydroxymethylglutaryl-CoA Reductase Inhibitors

Keywords

  • Endothelial nitric oxide synthase
  • Inducible nitric oxide synthase
  • Peroxisome proliferator-activated receptor-γ

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice. / Ye, Yumei; Lin, Yu; Manickavasagam, Saraswathy; Perez-Polo, J. Regino; Tieu, Brian C.; Birnbaum, Yochai.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 295, No. 6, 12.2008.

Research output: Contribution to journalArticle

Ye, Yumei ; Lin, Yu ; Manickavasagam, Saraswathy ; Perez-Polo, J. Regino ; Tieu, Brian C. ; Birnbaum, Yochai. / Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice. In: American Journal of Physiology - Heart and Circulatory Physiology. 2008 ; Vol. 295, No. 6.
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AU - Tieu, Brian C.

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N2 - Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-γ agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA2 and COX2, and increases myocardial 6-keto-PGF 1α levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS-/- and iNOS-/- mice. Male C57BL/6 wild-type (WT), eNOS-/-, and iNOS-/- mice received 10 mg·kg-1·day-1 Pio (Pio+) or water alone (Pio-) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4 ± 1.4% vs. 39.0 ± 1.1%; P < 0.001), as well as in the eNOS-/- (32.0 ± 1.6% vs. 44.2 ± 1.9%; P < 0.001) and iNOS-/- (18.0 ± 1.2% vs. 45.5 ± 2.3%; P < 0.001) mice. The protective effect of Pio in eNOS-/- mice was smaller than in the WT (P < 0.001) and iNOS -/- (P < 0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS-/- mice. iNOS was undetectable in all six groups. Pio increased cPLA2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS-/- and iNOS-/-, mice. Pio increased the myocardial 6-keto-PGF 1α levels and cPLA2 and COX2 activity in the WT, eNOS-/-, and iNOS-/- mice. In conclusion, the myocardial protective effect of Pio is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized.

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