Cardiac-Specific Expression of the Tetracycline Transactivator Confers Increased Heart Function and Survival Following Ischemia Reperfusion Injury

Elsherif, Laila; Wang, Xuerong; Grachoff, Milana; Wolska, Beata M.; Geenen, David L.; O’Bryan, John P.

doi:10.1371/journal.pone.0030129

Cited by 7 publications

(5 citation statements)

References 21 publications

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“…PI3K inhibitor LY294002 injection aggravated these conditions in LYLI pig hearts; however, IP offset this effect maximally in IPLI pigs that received IP but not LY294002 injection before AMI induction. This suggests that the cardioprotective effect of IP protected against adverse left ventricular remodeling in pigs after MI, and the PI3K inhibitor LY294002 can diminish this cardioprotective effect, in agreement with the study of Elsherif et al 14 showing that PI3K inhibitors (wortmannin and LY294002) abolish the protection of IP.…”

Section: Pi3k Inhibitor Ly294002 Diminished Ip-induced Antiarrhythmiasupporting

confidence: 90%

Cardioprotection by PI3K-mediated signaling is required for anti-arrhythmia and myocardial repair in response to ischemic preconditioning in infarcted pig hearts

Zhao

Zhang

Wang

et al. 2015

Laboratory Investigation

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Although the phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway is essential for conferring cardioprotection in response to ischemic preconditioning (IP), the role of PI3K/Akt signaling in the infarcted heart for mediating the anti-arrhythmic effects in response to IP remains unclear. We explored the involvement of PI3K/Akt in the IP-like effect of connexin 43 and proangiogenic factors with particular regard to its role in protecting against ischemia-induced arrhythmia, heart failure, and myocardial remodeling. Groups of pigs were administered phosphate-buffered saline (PBS) or LY294002 solution. Before induction of myocardial infarction (MI), pigs were grouped according to whether or not they underwent IP. Next, all animals underwent MI induction by ligation of the left anterior descending (LAD) coronary artery. Myocardial tissues from the pig hearts at 7 days after MI were used to assess myocardium myeloperoxidase and reaction oxygen species, infarct size, collagen content, blood vascular density, expression of Akt, connexin 43, and proangiogenic growth factors, using spectrophotometer, histology, immunohistochemistry, real-time RT-PCR, and western blot. At 7 days after MI, IP significantly reduced animal mortality and malignant ventricular arrhythmia, myocardial inflammation, infarct size, and collagen content, and improved cardiac function and remodeling; use of the PI3K inhibitor LY294002 diminished these effects. In parallel with a decline in Akt expression and phosphorylation by MI, LY294002 injection resulted in significant suppression of connexin 43 and proangiogenic factor expression, and a reduction of angiogenesis and collateral circulation. These findings demonstrate that the cardioprotective effects of IP on antiventricular arrhythmia and myocardial repair occur through upregulation of PI3K/Akt-mediated connexin 43 and growth factor signaling. Sudden cardiac death comprises over 10% of all deaths from natural causes and constitutes a major health-related problem worldwide. In ∼ 80% of cases, sudden cardiac death is caused by sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) secondary to acute myocardial infarction (AMI). 1 Reducing malignant ventricular arrhythmia in infarcted hearts may be a key factor for improving prognosis of patients with MI. The strategy of myocardial repair using ischemic preconditioning (IP) provides an enticing option to reduce the severity of arrhythmias associated with AMI. Since its first description, myocardial IP has been found to enhance cardiac electrical stability in both animals and humans. However, the precise antiarrhythmic mechanisms underlying this adaptive process during ischemia are not well understood. It is generally thought that IP is able to limit the mass of myocardium at risk that ultimately becomes infarcted and results in reducing lethal arrhythmia. 2,3 However, lack of IP enhanced inflammatory response, and subsequent left ventricle (LV) dysfunction, are related to VT/VF development after AMI. 4 It has also been reported that c...

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Section: Pi3k Inhibitor Ly294002 Diminished Ip-induced Antiarrhythmiasupporting

confidence: 90%

Cardioprotection by PI3K-mediated signaling is required for anti-arrhythmia and myocardial repair in response to ischemic preconditioning in infarcted pig hearts

Zhao

Zhang

Wang

et al. 2015

Laboratory Investigation

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“…According to references and a preliminary study [9], [10], a model was constructed by occluding the left coronary artery for 45 min followed by 2 h of reperfusion. This model could closely simulate acute myocardial I/R injury.…”

Section: Methodsmentioning

confidence: 99%

Protective Role of Deoxyschizandrin and Schisantherin A against Myocardial Ischemia–Reperfusion Injury in Rats

Chang

Yang

et al. 2013

PLoS ONE

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BackgroundOur previous studies suggested that deoxyschizandrin (DSD) and schisantherin A (STA) may have cardioprotective effects, but information in this regard is lacking. Therefore, we explored the protective role of DSD and STA in myocardial ischemia–reperfusion (I/R) injury.Methodology/Principal FindingsAnesthetized male rats were treated once with DSD and STA (each 40 µmol/kg) through the tail vein after 45 min of ischemia, followed by 2-h reperfusion. Cardiac function, infarct size, biochemical markers, histopathology and apoptosis were measured and mRNA expression of gp91phox in myocardial tissue assessed by RT-PCR. Neonatal rat cardiomyocytes were pretreated with DSD and STA and then damaged by H2O2. Cell apoptosis was tested by a flow cytometric assay. Compared with the I/R group: (i) DSD and STA could significantly reduce the abnormalities of LVSP, LVEDP, ±dp/dtmax and arrhythmias, thereby showing their protective roles in cardiac function; (ii) DSD and STA could significantly attenuate the infarct size and MDA release while increasing SOD activity, suggesting a role in reducing myocardial injury; (iii) tissue morphology and myocardial textual analysis revealed that DSD and STA mitigated changes in myocardial histopathology; (iv) DSD and STA decreased apoptosis (33.56±2.58% to 10.28±2.80% and 10.98±1.99%, respectively) and caspase-3 activity in the myocardium (0.62±0.02 OD/mg to 0.38±0.02 OD/mg and 0.32±0.02 OD/mg, respectively), showing their protective effects upon cardiomyocytes; and (v) DSD and STA had similar protective effects on I/R injury as those seen with the positive control metoprolol. In vitro, DSD and STA could significantly decrease the apoptosis of neonatal cardiomyocytes.Conclusions/SignificanceThese data suggest that DSD and STA can protect against myocardial I/R injury. The underlining mechanism may be related to their role in inhibiting cardiomyocyte apoptosis.

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“…As has been previously described, model was constructed by occluding the left coronary artery for 30 minutes followed by 2 hours of reperfusion, which closely simulates acute myocardial I/R injury ( 17 , 18 ). In brief, rats were anesthetized intraperitoneally with 1 g/kg urethane.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction

et al. 2016

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Objective:The goal of the present study was to investigate the effects of 5-lipoxygenase (5-LOX) inhibition, alone and with cyclooxygenase (COX) inhibitors, on inflammatory parameters and apoptosis in ischemia/reperfusion (I/R)-induced myocardial damage in rats. For this purpose, zileuton, a selective and potent inhibitor of 5-LOX, resulting in suppression leukotriene production, was used.Methods:Male Wistar rats (200-250 g; n=12 per group) were used in the study. I/R was performed by occluding the left coronary artery for 30 minutes and 2 hours of reperfusion of the heart. Experimental groups were I/R group, sham I/R group, zileuton (5 mg/kg orally, twice daily)+I/R group, zileuton+indomethacin (5 mg/kg intraperitoneally)+I/R group, zileuton+ketorolac (10 mg/kg subcutaneously)+I/R group, and zileuton+nimesulide (5 mg/kg subcutaneously)+I/R group. Following I/R, blood samples were collected to measure tumor necrosis factor alpha (TNF-α), and left ventricles were excised for evaluation of microscopic damage; malondialdehyde (MDA), glutathione, nuclear factor (NF)-κB assays; and evaluation of apoptosis.Results:Left ventricle MDA in I/R group was higher compared to sham group; however, it did not show significant change with zileuton. Although tissue injury in I/R group was less severe in all treatment groups, it was not statistically significant. NF-κB H-score and apoptotic index, which were higher in I/R group compared to sham I/R, were decreased with application of zileuton (H-score: p<0.01; apoptotic index: p<0.001). Zileuton had no significant effect on increased serum TNF-α levels in I/R group.Conclusion:5-LOX inhibition in rat myocardial infarction model attenuated increased left ventricle NF-κB expression and apoptosis and these actions were not modulated by COX inhibitors. (Anatol J Cardiol 2017; 17: 269-75)

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Cardiac-Specific Expression of the Tetracycline Transactivator Confers Increased Heart Function and Survival Following Ischemia Reperfusion Injury

Cited by 7 publications

References 21 publications

Cardioprotection by PI3K-mediated signaling is required for anti-arrhythmia and myocardial repair in response to ischemic preconditioning in infarcted pig hearts

Cardioprotection by PI3K-mediated signaling is required for anti-arrhythmia and myocardial repair in response to ischemic preconditioning in infarcted pig hearts

Protective Role of Deoxyschizandrin and Schisantherin A against Myocardial Ischemia–Reperfusion Injury in Rats

Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction

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