Cardioprotection against myocardial infarction with PTD-BIR3/RING, a XIAP mimicking protein

Souktani, Rachid; Pons, Sandrine; Guégan, Christelle; Bouhidel, Omar; Bruneval, Patrick; Zini, Roland; Mandet, Chantal; Onténiente, Brigitte; Berdeaux, Alain; Ghaleh, Bijan

doi:10.1016/j.yjmcc.2009.02.005

Cited by 20 publications

(12 citation statements)

References 36 publications

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“…Previous studies showed that XIAP expression in myocardial tissue was reduced after ischemia or hypoxia (Lyn et al 2002). The administration of pharmacologically mimicking endogenous XIAP, PTD-BIR3/RING, reduces myocardial infarct size when injected during reperfusion through interruption of caspase activation (Souktani et al 2009). These results suggested that Fig.…”

Section: Discussionmentioning

confidence: 99%

“…X-linked inhibitor of apoptosis protein (XIAP) is the best characterized and most potent endogenous regulators of apoptotic cell death in mammals (Holcik et al 2001). Many results revealed that it was a major inhibitor of apoptosis in cardiomyocytes (Potts et al 2005;Souktani et al 2009). Our primary results found decreased cardiac expression of XIAP in aging rats, and Li et al found a downregulated XIAP expression in aging transgenic mice hearts (Li and Ren 2007).…”

Section: Introductionmentioning

confidence: 99%

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Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death

Wang

Zhang

Liu

et al. 2012

AGE

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Survival after acute myocardial infarction is decreased in elderly patients. The enhanced rates of apoptosis in the aging heart exacerbate myocardial ischemia/reperfusion (MI/R) injury. We have recently demonstrated that the X-linked inhibitor of apoptosis protein (XIAP), the most potent endogenous inhibitor of apoptosis, was decreased in aging rats' hearts. XIAP was balanced by two mitochondria proteins, Omi/HtrA2 and Smac/DIABLO. However, the implicative role of XIAP, Omi/HtrA2, and Smac/DIABLO to aging-related MI/R injury has not been previously investigated. In our study, male aging rats (20-24 months) or young adult rats (4-6 months) were subjected to 30 min of myocardial ischemia followed by reperfusion. MI/R-induced cardiac injury was enhanced in aging rats, as evidenced by aggravated cardiac dysfunction, enlarged infarct size, and increased myocardial apoptosis (TUNEL and caspase-3 activity). Then, the XIAP, Omi/HtrA2, and Smac/ DIABLO protein and mRNA expression was detected. XIAP protein and mRNA expression was decreased in both aging hearts and aging hearts subjected to MI/R. Meanwhile, myocardial XIAP protein expression was correlated to cardiac function after MI/R. However, Omi/HtrA2, but not Smac/DIABLO, expression was increased in aging hearts. Moreover, the translocation of Omi/HtrA2 from mitochondria to cytosol was increased in both aging hearts and aging hearts subjected to MI/R. Treatment with ucf-101 (a novel and specific Omi/HtrA2 inhibitor) attenuated XIAP degradation and caspase-3 activity and exerted cardioprotective effects. Taken together, these results demonstrated that increased expression and leakage of Omi/HtrA2 enhanced MI/R injury in aging hearts via degrading XIAP and promoting myocardial apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death

Wang

Zhang

Liu

et al. 2012

AGE

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“…Caspase 3 activity was assayed from cardiac samples, as previously described. 24 Briefly, tissues were homogenized in cold buffer (25 mmol/L HEPES, pH 7.5, 5 mmol/L MgCl 2 , 2 mmol/L EDTA, 0.1% Triton X-100, 2 mmol/L dithiothreitol, 1 mmol/L phenylmethanesulfonyl fluoride, 5 L/mL protease cocktail inhibitor P8340; Sigma-Aldrich, St. Louis, MO). Homogenates were centrifuged and supernatants collected.…”

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Ultrafast and Whole-Body Cooling With Total Liquid Ventilation Induces Favorable Neurological and Cardiac Outcomes After Cardiac Arrest in Rabbits

et al. 2011

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Background-In animal models of cardiac arrest, the benefit afforded by hypothermia is closely linked to the rapidity of the decrease in body temperature after resuscitation. Because total liquid ventilation (TLV) with temperature-controlled perfluorocarbons induces a very rapid and generalized cooling, we aimed to determine whether this could limit the post-cardiac arrest syndrome in a rabbit model. We especially focused on neurological, cardiac, pulmonary, liver and kidney dysfunctions. Methods and Results-Anesthetized rabbits were submitted to either 5 or 10 minutes of untreated ventricular fibrillation.After cardiopulmonary resuscitation and resumption of a spontaneous circulation, the animals underwent either normothermic life support (control) or therapeutic hypothermia induced by TLV. The latter procedure decreased esophageal and tympanic temperatures to 32°C to 33°C within only 10 minutes. After rewarming, the animals submitted to TLV exhibited an attenuated neurological dysfunction and decreased mortality 7 days later compared with control. The neuroprotective effect of TLV was confirmed by a significant reduction in brain histological damages. We also observed limitation of myocardial necrosis, along with a decrease in troponin I release and a reduced myocardial caspase 3 activity, with TLV. The beneficial effects of TLV were directly related to the rapidity of hypothermia induction because neither conventional cooling (cold saline infusion plus external cooling) nor normothermic TLV elicited a similar protection. Conclusions-Ultrafast cooling instituted by TLV exerts potent neurological and cardiac protection in an experimental model of cardiac arrest in rabbits. This could be a relevant approach to provide a global and protective hypothermia against the post-cardiac arrest syndrome. (Circulation. 2011;124:901-911.)Key Words: cardiopulmonary resuscitation Ⅲ fibrillation Ⅲ heart arrest Ⅲ ischemia Ⅲ ventilation I nstitution of mild therapeutic hypothermia (32°C to 34°C) during 24 to 36 hours after resuscitation is known to improve survival and neurological recovery in comatose survivors of cardiac arrest. 1,2 However, experimental studies in dogs, 3,4 pigs, 5,6 and rodents 7,8 demonstrated that the neuroprotection afforded by hypothermia was related to the rapidity of the decrease in body temperature after resuscitation. When achieved rapidly, hypothermia could also be beneficial for other organs because, for example, it can also be potently cardioprotective during myocardial ischemia. 9 -12 Accordingly, many strategies were proposed to afford such a rapid hypothermia, including intravenous infusion of cold fluid 13 and endovascular 14 or intranasal cooling. 15,16 Clinical Perspective on p 911Another strategy that can experimentally provide very rapid and generalized cooling is liquid ventilation of the lungs with temperature-controlled perfluorocarbons. 11,[17][18][19][20][21][22] These liquids can use the lungs as heat exchangers while maintaining normal gas exchanges. 18 -20 In addition, this ven...

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“…Previous in vivo reports have clearly demonstrated that the beneficial effects of several cardioprotective strategies were observed with short but not with long durations of reperfusion. 37,38 In contrast, it is still possible to reduce myocardial infarct size when a drug or strategy is applied late during reperfusion [39][40][41][42] suggesting that long periods of reperfusion are needed to observe the final extent of damage and to determine the real potency of a cardioprotective strategy. We used Trypan blue to assess cell viability.…”

Section: Discussionmentioning

confidence: 99%

A Model of Hypoxia-Reoxygenation on Isolated Adult Mouse Cardiomyocytes

Portal

Martin

Assaly

et al. 2013

J Cardiovasc Pharmacol Ther

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The use of in vitro experimental models of hypoxia-reoxygenation (H/R) that mimic in vivo ischemia-reperfusion represents a powerful tool to investigate cardioprotective strategies against myocardial infarction. Most in vitro studies are performed using neonatal cardiac cells or immortalized embryonic cardiac cell lines which may limit the extrapolation of the results. We developed an H/R model using adult cardiomyocytes freshly isolated from mice and compared its characteristics to the in vivo ischemia-reperfusion conditions. First, cell death was assessed at different values of pH medium during hypoxia (6.2 vs 7.4) to simulate extracellular pH during in vivo ischemia. Cardiomyocyte mortality was aggravated with hypoxia under acidic pH. We next evaluated the relationship between the duration of hypoxia and cell death. Hypoxia time-dependently reduced myocyte viability (-24%, -36%, -53%, and -74% with 1, 1.5, 2, and 3 hours of hypoxia followed by 17 hours of reoxygenation, respectively). We then focused on the duration of reoxygenation as cardioprotective strategies have been reported to have different effects with short and long durations of reperfusion. We observed that cardiomyocyte mortality was increased when the duration of reoxygenation was increased from 2 h to 17 hours. Finally, we used our characterized model to investigate the cardioprotective effect of regular treadmill exercise. Myocyte viability was significantly greater in exercised when compared to sedentary mice (44% and 26%, respectively). Similarly, mice submitted to in vivo ischemia-reperfusion elicited infarct sizes reaching 27%, 43%, and 55% with 20, 30, and 45 minutes of coronary artery occlusion. In addition, infarct size was significantly reduced by exercise. In conclusion, this H/R model of cardiomyocytes freshly isolated from adult mice shows similar characteristics to the in vivo ischemia-reperfusion conditions. The comparison of in vivo and in vitro settings represents a powerful approach to investigate cardioprotective strategies and to distinguish between direct and indirect cardiomyocyte-dependent mechanisms.

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Cardioprotection against myocardial infarction with PTD-BIR3/RING, a XIAP mimicking protein

Cited by 20 publications

References 36 publications

Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death

Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death

Ultrafast and Whole-Body Cooling With Total Liquid Ventilation Induces Favorable Neurological and Cardiac Outcomes After Cardiac Arrest in Rabbits

A Model of Hypoxia-Reoxygenation on Isolated Adult Mouse Cardiomyocytes

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