Simvastatin-induced myocardial protection against ischemia–reperfusion injury is mediated by activation of ATP-sensitive K+ channels

Tavackoli, Shahin; Ashitkov, Taras V.; Hu, Zhao; Motamedi, Massoud; Uretsky, Barry F.; Birnbaum, Yochai

doi:10.1097/00019501-200402000-00008

Cited by 32 publications

(31 citation statements)

References 64 publications

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“…Subcutaneous 0.1 mg/kg buprenorphine was administered, the chest was closed, and the mice were recovered from anesthesia. Four hours after reperfusion, the mice were reanesthetized, the coronary artery was reoccluded, Evans blue dye (3%) was injected into the right ventricle, and the mice were euthanized under deep anesthesia (2,7,54,69).…”

Section: Infarct Sizementioning

confidence: 99%

“…Slices were incubated for 10 min at 37°C in 1% buffered (pH ϭ 7.4) 2,3,5-triphenyltetrazolium chloride, fixed in a 10% formaldehyde, and photographed to identify the AR (uncolored by the blue dye), the IS (unstained by 2,3,5-triphenyltetrazolium chloride), and the nonischemic zones (colored by blue dye). The AR and IS in each slice were determined by planimetry, converted into percentages of the whole for each slice, and multiplied by the weight of the slice, and the results were summed to obtain the weight of the myocardial AR and IS (2,7,54,69).…”

Section: Determination Of Ar and Ismentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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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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Section: Infarct Sizementioning

confidence: 99%

Section: Determination Of Ar and Ismentioning

confidence: 99%

mentioning

confidence: 99%

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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

Self Cite

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“…Subcutaneous 0.1 mg/kg buprenorphine was administered, the chest was closed, and the mice were recovered from anesthesia. Four hours after reperfusion, the mice were reanesthetized, the coronary artery was reoccluded, Evans blue dye (3%) was injected into the right ventricle, and the mice was euthanized under deep anesthesia (2,7,43,53).…”

mentioning

confidence: 99%

The role of eNOS, iNOS, and NF-κB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin

Martinez

Perez‐Polo³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Ye Y, Martinez JD, Perez-Polo RJ, Lin Y, Uretsky BF, Birnbaum Y. The role of eNOS, iNOS, and NF-B in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin. Am J Physiol Heart Circ Physiol 295: H343-H351, 2008. First published May 9, 2008 doi:10.1152/ajpheart.01350.2007.-Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-B dependent. Male C57BL/6 wild-type (WT), University of North Carolina eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ mice received ATV (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ; ATV ϩ ) or water alone (ATV Ϫ ) for 3 days. Mice underwent 30 min of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-B in WT mice. It also increased myocardial COX2 activity. In eNOS Ϫ/Ϫ mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-B was not activated by ATV in the eNOS Ϫ/Ϫ mice. In the iNOS Ϫ/Ϫ mice, eNOS and p-eNOS levels were increased but not iNOS and COX2 levels; however, NF-B was activated. In conclusion, both eNOS and iNOS are essential for the IS-limiting effect of ATV. The expression of COX2 by ATV is iNOS, but not eNOS or NF-B, dependent. Activation of COX2 is dependent on iNOS. endothelial nitric oxide synthase; inducible nitric oxide synthase; nuclear factor-B THE 3-HYDROXY-3-METHYLGLUTARYL coenzyme A (HMG-CoA) reductase inhibitors (statins) protect against ischemia-reperfusion injury and, when administered before ischemia (2, 5, 7, 25, 26, 34 -36, 43, 44, 46 -48, 52, 53) or immediately upon reperfusion (4, 17, 47), limit myocardial infarct size (IS) in various animal models. Several investigators have shown that the activation of endothelial nitric oxide synthase (eNOS) is essential for this protective effect, since nonspecific nitric oxide synthase (NOS) inhibitors blunt the IS-limiting effect of statins (5, 48) and since statins do not reduce IS in eNOS Ϫ/Ϫ mice (1, 4, 18, 25, 52). However, most of these studies used a particular eNOS Ϫ/Ϫ line (Harvard). As reported by Sharp et al. (37), there are two distinct lines of eNOS Ϫ/Ϫ mice: the Harvard line lacks compensatory increases in inducible NOS (iNOS) and has an IS bigger than the corresponding wild-type (WT) mice, and the University of North Carolina line, which has compensatory increases in iNOS expression and an IS smaller than the corresponding WT mice. It has been suggested that iNOS can be protective and compensate for the lack in eNOS and that ...

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“…LAD-induced myocardial infarction was performed using a rat model described by Birnbaum et al (2003) and Tavackoli et al (2004). The rats were anesthetized with chloral hydrate (400 mg/kg, i.p.).…”

Section: Ischemia Reperfusion Injury-induced Myocardial Infarctionmentioning

confidence: 99%

Effect of ethanol extract ofEmbelia ribesfruits on cardiac changes in rats subjected to ischemic reperfusion injury

Ansari

Bhandari

Islam

et al. 2009

Pharmaceutical Biology

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Simvastatin-induced myocardial protection against ischemia–reperfusion injury is mediated by activation of ATP-sensitive K+ channels

Abstract: Simvastatin significantly reduced myocardial infarct size. The protective effect was completely abrogated by glyburide, strongly suggesting that this protective effect is mediated via activation of the ATP-sensitive K channels.

Cited by 32 publications

References 64 publications

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

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

The role of eNOS, iNOS, and NF-κB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin

Effect of ethanol extract ofEmbelia ribesfruits on cardiac changes in rats subjected to ischemic reperfusion injury

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