Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia

Xi, Lei; Tekin, Demet; Gursoy, Erdal; Salloum, Fadi N.; Levasseur, Joseph E.; Kukreja, Rakesh C.

doi:10.1152/ajpheart.00920.2001

Cited by 67 publications

(62 citation statements)

References 47 publications

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“…Similar to sublethal ischemia, hypoxia elicits PC-like response in which the myocardium develops an adaptive phenotype leading to resistance against subsequent lethal I/R injuries (Meerson et al, 1973;Bolli, 2000;Xi et al, 2002). This cardioprotection seems to be essentially mediated by hypoxia-inducible factor 1␣ (HIF-1␣) (Cai et al, 2003).…”

Section: Mirnas In Hypoxic Preconditioningmentioning

confidence: 99%

MicroRNAs: New Players in Cardiac Injury and Protection

Kukreja¹,

Yin²,

Salloum³

2011

Mol Pharmacol

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122

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MicroRNAs (miRNAs) have emerged as a novel class of endogenous, small, noncoding RNAs that negatively regulate gene expression via degradation or translational inhibition of their target mRNAs. Over 700 miRNAs have been identified and sequenced in humans, and the number of miRNA genes is estimated at more than 1000. Individual miRNA is functionally important as a transcription factor because it has the ability to regulate the expression of multiple genes through binding to its target with imperfect or perfect complement. In the heart, miRNAs have been involved in several clinical scenarios, such as ischemia/reperfusion (I/R) injury and heart failure suggesting that regulation of their function could be used as a novel cardioprotective strategy. In particular, miRNA-1, miRNA-21, miRNA-24, miRNA-29, miRNA-92a, miRNA-126, miRNA-133, miRNA-320, miRNA-199a, miRNA-208, and miRNA-195 have been shown to be regulated after I/R injury. Because tissue miRNAs can be released into circulating blood, they also offer exciting new opportunities for developing sensitive biomarkers, including miRNA-1, miRNA-126, miR-208, and miRNA-499, for acute myocardial infarction and other cardiac diseases.

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Section: Mirnas In Hypoxic Preconditioningmentioning

confidence: 99%

MicroRNAs: New Players in Cardiac Injury and Protection

Kukreja¹,

Yin²,

Salloum³

2011

Mol Pharmacol

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122

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“…Hypoxic preconditioning (PC), like ischemic PC [9] can provide delayed protection against ischemia-reperfusion injury [10,11]. IH for 4 hrs with 10% O 2 induces cardioprotection illustrated by a reduction of infarct size in isolated rat heart [8].…”

Section: Introductionmentioning

confidence: 99%

Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2

Béguin

Belaidi

Godin‐Ribuot

et al. 2007

Journal of Molecular and Cellular Cardiology

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. Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2.. Journal of Molecular and Cellular Cardiology, Elsevier, 2007, 42 (2) AbstractObjective. We previously reported that acute intermittent hypoxia (IH) confers delayed cardioprotection against a prolonged ischemic insult in the rat, via the involvement of nitric oxide synthase and K ATP channels. In the present study, we investigated the role of protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K), stress activated p38 MAP kinase (MAPK) and extracellular signal regulated kinase (ERK1/2) using selective inhibitors of these pathways. Methods. Adult male rats were exposed to 1-min cycles of IH (10% O 2 , 40 sec) / normoxia (21% O 2 , 20 sec) during 4 hrs or to normoxic cycles. 24 hrs later, isolated hearts were perfused in Langendorff mode and subjected to a 30-min global ischemia followed by 120 min of reperfusion. Results. Compared to normoxic conditions, IH significantly reduced infarct size (22.2  2.4% vs 33.8  2.6%, p<0.05), improved coronary flow and decreased the contracture at reperfusion. When administered before sustained ischemia, chelerythrine (a PKC inhibitor) abolished both the IH-induced reduction in infarct size (36.1  4.9%) and improvement in hemodynamic parameters. In contrast, chelerythrine administration 10 min before IH, did not modify the delayed cardioprotective response. Similarly, wortmannin (a PI3K inhibitor) administration 10 min before IH was unable to block the cardioprotective effects. However, administration of SB203580 (a p38 MAPK inhibitor) and PD98059 (an Erk1/2 inhibitor), 30 min before IH abolished its delayed infarct-sparing effect (32.2  3.4% and 33.9  2.9% respectively). In addition, 24 hrs after IH, a significant increase in p38 MAPK and Erk1/2 phosphorylation was observed by Western blot. Conclusion. These results suggest that the delayed preconditioning induced by intermittent hypoxia does not involve the PI3K signalling pathway and that is mediated by PKC and triggered by p38 MAPK and Erk1/2.

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“…A variety of other stimuli, such as hypoxia, thermal stress, pharmacologic agents, and endogenous triggers of preconditioning such as nitric oxide and adenosine have also been shown to induce cardioprotective effects in several animal species (7)(8)(9)(10). Also, recent studies from our laboratory have shown that sildenafil citrate (Viagra), a selective PDE-5 inhibitor, induces powerful preconditioninglike protective effects in the ischemic heart (11).…”

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confidence: 99%

Sildenafil Citrate (Viagra) Induces Cardioprotective Effects after Ischemia/Reperfusion Injury in Infant Rabbits

et al. 2005

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Infants undergoing surgery for congenital heart disease are at risk for myocardial ischemia during cardiopulmonary bypass, circulatory arrest, or low-flow states. The purpose of this study was to demonstrate the effects of sildenafil, a selective phosphodiesterase-5 (PDE-5) inhibitor on myocardial functional improvement and infarct size reduction during ischemia/reperfusion injury in infant rabbits. Infant rabbits (aged 8 wk) were treated with sildenafil citrate (0.7 mg/kg i.v.) or normal saline 30 min before sustained ischemia for 30 min and reperfusion for 3 h. Transesophageal echocardiography (TEE) was used to assess left ventricular cardiac output (LVCO) and aortic velocity time integral (VTI). After ischemia/reperfusion, risk area was demarcated by Evan's blue dye and infarct size determined by computer morphometry of triphenyltetrazolium chloride-stained sections. The sildenafil-treated group had preservation and elevation in LVCO (143% of baseline, p Ͻ 0.05) and an elevated aortic VTI (145% of baseline, p Ͻ 0.05) after 30 min of ischemia compared with the control group LVCO (72% of baseline, p Ͻ 0.05) and aortic VTI (73% of baseline, p Ͻ 0.05). This is a statistically significant increase in LVCO and aortic VTI in the sildenafil group compared with controls (n ϭ 6/group, p Ͻ 0.05).The sildenafil-treated group had significant reduction in infarct size (15.5 Ϯ 1.2 versus 33 Ϯ 2.3 in the saline group, % risk area, mean Ϯ SEM, n ϭ 10 -15/group, p Ͻ 0.05). For the first time, we have shown that sildenafil citrate promotes myocardial protection in infant rabbits as evidenced by postischemic preservation and elevation in LVCO and aortic VTI and reduction in infarct size. Each year, more than 25,000 children undergo corrective surgery for congenital heart disease. Early surgical intervention is important to promote more normal development. Infants undergoing surgery for congenital heart disease are at risk for myocardial ischemia during cardiopulmonary bypass, circulatory arrest, or low-flow states (1). Less is known about the tolerance of the infant myocardium to ischemia compared with the adult, and cardiac reserves are more limited in the infant (2). Although there is evidence that the infant myocardium may be more resilient to metabolic or ischemic injury compared with adults, the infant heart responds quite differently to cardiovascular drugs, stress, and changes in hemodynamics (3,4). Although hypothermia combined with pharmacologic cardioplegia protects the globally ischemic adult heart, this benefit may not extend to infants. For example, poor postischemic recovery of function and increased mortality may result when this method of myocardial protection is used in children (5). Therefore, there is a need to develop novel pharmacological approaches to protect infant hearts from ischemia/ reperfusion injury.Brief episodes of ischemia protect the myocardium from more prolonged periods of ischemia, a phenomenon called ischemic preconditioning (6). A variety of other stimuli, such

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Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia

Cited by 67 publications

References 47 publications

MicroRNAs: New Players in Cardiac Injury and Protection

MicroRNAs: New Players in Cardiac Injury and Protection

Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2

Sildenafil Citrate (Viagra) Induces Cardioprotective Effects after Ischemia/Reperfusion Injury in Infant Rabbits

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