Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia?reperfusion injury

Birnbaum, Yochai; Ye, Yumei; Rosanio, Salvatore; Tavackoli, Shahin; Hu, Zhao; Schwarz, Ernst R.; Uretsky, Barry F.

doi:10.1016/j.cardiores.2004.10.018

Cited by 127 publications

(145 citation statements)

References 55 publications

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“…The effect of SIM on infarct size in this study is consistent with that found in previous studies because 2 mg/kg of SIM in pigs is approximately equivalent to 10 mg/kg in rats, after correction for body surface area [15] . The infarct-limitation effect of statins in ischemiareperfusion is mainly attributed to its pleiotropic effects via the PI3K/Akt/eNOS pathway because the effects of the statins can be abolished by inhibiting PI3K or eNOS [5][6][7][8][9] . In this study, we further found that acute pretreatment with single-dose SIM not only decreased the infarct size but also attenuated the no-reflow area, and we showed that the PKA pathway was another important mediator in the cardioprotection of SIM that acts by modulating the phosphorylation of eNOS at Ser 1179 and Ser 635 .…”

Section: Discussionmentioning

confidence: 99%

“…Enhancing Ser 1177/1179 phosphorylation via the PI3K/Akt pathway is considered to be the main mechanism by which statins protect against ischemia-reperfusion injury [5][6][7][8][9] . However, several lines of evidence have shown that PKA also regulates the phosphorylation of eNOS at Ser 1179 , Ser 635 , and Ser 617 in bovine eNOS (Ser 1177 , Ser 633 , and Ser 615 in humans) [24,[26][27][28][29] .…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that chronic and early pretreatment with statins can improve coronary circulation and reduce the sizes of no-reflow and infarct after ischemia-reperfusion injury by enhancing endothelial (e-)nitric oxide synthase (eNOS) activ-ity through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling cascade [4][5][6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Yang

Geng³

et al. 2012

Acta Pharmacol Sin

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Aim: The cholesterol-lowering drugs statins could enhance the activities of endothelial nitric oxide synthase (eNOS) and protect myocardium during ischemia and reperfusion. The aim of this study was to examine whether protein kinase A (PKA) was involved in statinmediated eNOS phosphorylation and cardioprotection. Methods: 6-Month-old Chinese minipigs (20-30 kg) underwent a 1.5-h occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD). In the sham group, the LAD was encircled by a suture but not occluded. Hemodynamic and cardiac function was monitored using a polygraph. Plasma activity of creatine kinase and the tissue activities of PKA and NOS were measured spectrophotometrically. p-CREB, eNOS and p-eNOS levels were detected using Western blotting. Sizes of the area at risk, the area of no-reflow and the area of necrosis were measured morphologically. Results: Pretreatment of the animals with simvastatin (SIM, 2 mg/kg, po) before reperfusion significantly decreased the plasma activity of creatine kinase, an index of myocardial necrosis, and reduced the no-reflow size (from 50.4%±2.4% to 36.1%±2.1%, P<0.01) and the infarct size (from 79.0%±2.7% to 64.1%±4.5%, P<0.01). SIM significantly increased the activities of PKA and constitutive NOS, and increased Ser 133 p-CREB protein, Ser 1179 p-eNOS, and Ser 635 p-eNOS in ischemic myocardium. Intravenous infusion of the PKA inhibitor H-89 (1 μg·kg -1 ·min -1 ) partially abrogated the SIM-induced cardioprotection and eNOS phosphorylation. In contrast, intravenous infusion of the eNOS inhibitor L-NNA (10 mg·kg -1 ) completely abrogated the SIM-induced cardioprotection and eNOS phosphorylation during ischemia and reperfusion, but did not affect the activity of PKA. Conclusion: Pretreatment with a single dose of SIM 2.5 h before reperfusion attenuates myocardial no-reflow and infarction through increasing eNOS phosphorylation at Ser 1179 and Ser 635 that was partially mediated via the PKA signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Yang

Geng³

et al. 2012

Acta Pharmacol Sin

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“…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).…”

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confidence: 99%

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

Ye¹,

Lin²,

Manickavasagam³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Ye Y, Lin Y, Manickavasagam S, Perez-Polo JR, Tieu BC, Birnbaum Y. Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice. Am J Physiol Heart Circ Physiol 295: H2436 -H2446, 2008. First published October 17, 2008 doi:10.1152/ajpheart.00690.2008.-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-␥ agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA 2 and COX2, and increases myocardial 6-keto-PGF1␣ levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ mice. Male C57BL/6 wild-type (WT), eNOS Ϫ/Ϫ , and iNOS Ϫ/Ϫ mice received 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 Pio (Pioϩ) or water alone (PioϪ) 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 Ϯ 1.4% vs. 39.0 Ϯ 1.1%; P Ͻ 0.001), as well as in the eNOS Ϫ/Ϫ (32.0 Ϯ 1.6% vs. 44.2 Ϯ 1.9%; P Ͻ 0.001) and iNOS Ϫ/Ϫ (18.0 Ϯ 1.2% vs. 45.5 Ϯ 2.3%; P Ͻ 0.001) mice. The protective effect of Pio in eNOS Ϫ/Ϫ mice was smaller than in the WT (P Ͻ 0.001) and iNOS Ϫ/Ϫ (P Ͻ 0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS Ϫ/Ϫ mice. iNOS was undetectable in all six groups. Pio increased cPLA 2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ , mice. Pio increased the myocardial 6-keto-PGF 1␣ levels and cPLA2 and COX2 activity in the WT, eNOS Ϫ/Ϫ , and iNOS Ϫ/Ϫ 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. endothelial nitric oxide synthase; inducible nitric oxide synthase; peroxisome proliferator-activated receptor-␥ PROTECTION AGAINST ischemia-reperfusion injury may have a potential benefit in three distinct clinical situations: 1) limiting reperfusion injury in patients presenting with ST-elevation acute myocardial infarction before undergoing reperfusion therapy; 2) short-to intermediate-term treatment before elective procedures that may pose a risk for myocardial ischemia, such as cardiac or noncardiac surgery or percutaneous coronary interventions; and 3) long-term treatment in patients with established coronary artery disease to minimize the damage from an effort-induced ischemia or a potential future myocardial infarction. In the present study we studied whether the myocardial protection effects of intermediate-term pretreatment with pioglitazone (Pio) is dependent on nitric oxide (NO) synthases (NOSs), using a model that may be relevant to the second option mentioned above....

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“…4S2005). For example, statins have been found to increase the generation of NO via eNOS activation (Laufs et al, 1997, Mital et al, 2000Landmesser et al, 2004), enhance the formation of prostanoids (Birnbaum et al, 2005) and induce heme-oxygenase-1 (Lee et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The effect of acute simvastatin administration on the severity of arrhythmias resulting from ischaemia and reperfusion in the canine: Is there a role for nitric oxide?

Kisvári

Kovács

Gardi

et al. 2014

European Journal of Pharmacology

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a b s t r a c tThe present study has examined the effects and the possible mechanisms of a single dose of simvastatin on the severity of arrhythmias resulting from a 25 min occlusion and reperfusion of the left anterior descending coronary artery in anaesthetized (chloralose and urethane) dogs. The control animals (n ¼16) were given the solvent of simvastatin by slow (over 5 min) intracoronary (ic.) injection just prior to the occlusion. Twenty-six dogs were treated with simvastatin (0.1 mg/kg) by the same route, both in the absence (n ¼15) and in the presence (n ¼11) of L-NAME. This latter was administered (5 mg/kg, ic.) either alone (n ¼12) or 10 min before the simvastatin treatment. The severity of ischaemia (epicardial STsegment, inhomogeneity) and ventricular arrhythmias (ventricular premature beats [VPBs], ventricular tachycardia [VT] and fibrillation [VF]), plasma nitrite/nitrate levels, myocardial superoxide production and eNOS activity were assessed. Compared with controls simvastatin significantly reduced the number of VPBs (289 7 34 vs. 947 25) and the episodes of VT (5.67 1.3 vs. 0.3 70.2), the incidence of VT (88% vs. 20%) and VF (56% vs. 0%) during occlusion and increased survival (0% vs. 33%) on reperfusion. There were also less marked ischaemic changes in the simvastatin-treated dogs than in the controls. Simvastatin preserved eNOS activity and nitric oxide (NO) bioavailability during occlusion and attenuated superoxide production following reperfusion. All these effects of simvastatin (except for the protection against VF) were reversed by L-NAME. We conclude that simvastatin given just prior to ischaemia/reperfusion reduces the severity of arrhythmias. This effect involves both NO-dependent and NO-independent mechanisms.

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Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia?reperfusion injury

Abstract: Our results suggest that the prostaglandins are essential for mediating the myocardial protective effects of ATV and their production is downstream to eNOS phosphorylation and iNOS.

Cited by 127 publications

References 55 publications

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

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

The effect of acute simvastatin administration on the severity of arrhythmias resulting from ischaemia and reperfusion in the canine: Is there a role for nitric oxide?

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