Antiapoptosis and Mitochondrial Effect of Pioglitazone Preconditioning in the Ischemic/reperfused Heart of Rat

Li, Jian; Lang, Mingjian; Mao, Xiaobo; Tian, Li; Feng, Yan

doi:10.1007/s10557-008-6115-x

Cited by 34 publications

(23 citation statements)

References 36 publications

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“…Supportingly, we found that inhibition of the MEK/ERK pathway abolished the hypoxia-induced increase in ⌬⌿ m . It is well established that reduction or loss of ⌬⌿ m is usually associated with apoptotic processes (10,14,22), whereas maneuvers preventing loss of ⌬⌿ m were shown to protect cells from apoptotic cell death (11,20,39). In this context our findings suggest that hypoxiainduced MEK/ERK activation, leading to phosphorylation and inactivation of the pro-apoptotic molecule Bad, results in a protection of mitochondrial membrane integrity by increasing ⌬⌿ m .…”

Section: Discussionsupporting

confidence: 53%

Transient hypoxia induces ERK-dependent anti-apoptotic cell survival in endothelial cells

Härtel

Holl

Arshad

et al. 2010

American Journal of Physiology-Cell Physiology

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Ischemia-induced apoptosis of endothelial cells may contribute to tissue injury, organ failure, and transplantation rejection. However, little is known about survival mechanisms capable to counteract endothelial apoptosis. This study investigated the potential role of an endogenous anti-apoptotic response elicited by transient hypoxia, capable to avert ongoing apoptosis in endothelial cells. Experiments were carried out in three different types of cultured endothelial cells (human umbilical vein, pig aorta, and from rat coronary microvasculature). As a pro-apoptotic challenge endothelial cells were cultured in serum-free medium and subjected to hypoxia for 2 h. We found that transient hypoxia reduced caspase 3 activation within 1 h of hypoxia. Accordingly, the number of apoptotic cells was reduced after 24 h of reoxygenation. This was true for all three cell types analyzed. Analysis of Akt and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways revealed that hypoxia induced a transient activation of ERK 2 but not of Akt. ERK 2 phosphorylation preceded the phosphorylation of pro-apoptotic molecule Bad at Ser112, an inhibitory phosphorylation site specific for ERK. The protective effects of hypoxia regarding Bad phosphorylation, caspase 3 activation, and apoptosis were abolished by MEK 1/2 inhibitors, PD98059 or UO126, as well as by antisense oligonucleotides directed against ERK 1/2. Furthermore, inhibition of this pathway inhibited hypoxia-induced increase in mitochondrial membrane potential. The present study demonstrates that transient hypoxia induces a novel survival mechanism that protects endothelial cells against apoptosis. This endogenous process involves MEK/ERK-mediated inhibition of the pro-apoptotic molecule Bad and caspase 3.

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Section: Discussionsupporting

confidence: 53%

Transient hypoxia induces ERK-dependent anti-apoptotic cell survival in endothelial cells

Härtel

Holl

Arshad

et al. 2010

American Journal of Physiology-Cell Physiology

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“…and that might have been improved by orally administered pioglitazone. The orally administered pioglitazone-induced angiogenic effect at peri-MI normal zone and/or antiapoptotic effect [32] might be essential for the survival of transdifferentiated cardiomyocytes. Improvement of survival of BM-MSCs in situ might also improve the effect of transplantation of BM-MSCs in this study.…”

Section: Study Limitationsmentioning

confidence: 99%

Pretreatment of Human Mesenchymal Stem Cells with Pioglitazone Improved Efficiency of Cardiomyogenic Transdifferentiation and Cardiac Function

et al. 2011

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The efficacy of transplantation of default human marrowderived mesenchymal stem cells (MSCs) was modest. In this study, our challenge was to improve the efficacy of MSC transplantation in vivo by pretreatment of MSCs with pioglitazone. MSCs were cultured with or without medium containing 1 lM of pioglitazone before cardiomyogenic induction. After cardiomyogenic induction in vitro, cardiomyogenic transdifferentiation efficiency (CTE) was calculated by immunocytochemistry using anti-cardiac troponin-I antibody. For the in vivo experiments, myocardial infarction (MI) at the anterior left ventricle was made in nude rats. Two weeks after MI, MSCs pretreated with pioglitazone (p-BM; n 5 30) or without pioglitazone (BM; n 5 17) were injected, and then survived for 2 weeks. We compared left ventricular function by echocardiogram and immunohistochemistry to observe cardiomyogenic transdifferentiation in vivo. Pretreatment with pioglitazone significantly increased the CTE in vitro (1.9% 6 0.2% n 5 47 vs. 39.5% 6 4.7% n 5 13, p < .05). Transplantation of pioglitazone pretreated MSCs significantly improved change in left ventricular % fractional shortening (BM; 24.8% 6 2.1%, vs. p-BM; 5.2% 6 1.5%). Immunohistochemistry revealed significant improvement of cardiomyogenic transdifferentiation in p-BM in vivo (BM; 0% 6 0% n 5 5, vs. p-BM; 0.077% 6 0.041% n 5 5). Transplantation of pioglitazonepretreated MSCs significantly improved cardiac function and can be a promising cardiac stem cell source to expect cardiomyogenesis.

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“…In some recent experimental studies using a rat model, treatment with pioglitazone before myocardial ischemia/ reperfusion reduced myocardial infarct size by attenuating reperfusion injury 34,35…”

Section: Pioglitazone and Myocardial Ischemia/reperfusion Injurymentioning

confidence: 99%

Use of pioglitazone in the treatment of diabetes: effect on cardiovascular risk

Zou¹,

Hu²

2013

VHRM

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Pioglitazone and other thiazolidinediones (TZDs) initially showed great promise as unique receptor-mediated oral therapy for type 2 diabetes, but a host of serious side effects, primarily cardiovascular, have limited their utility. It is crucial at this point to perform a risk– benefit analysis to determine what role pioglitazone should play in our current treatment of type 2 diabetes and where the future of this class of drugs is headed. This review provides a comprehensive overview of the present literature. Clinical data currently available indicate that pioglitazone is an effective and generally well-tolerated treatment option for use in patients with type 2 diabetes. Pioglitazone can still reduce adverse cardiovascular risk.

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Antiapoptosis and Mitochondrial Effect of Pioglitazone Preconditioning in the Ischemic/reperfused Heart of Rat

Abstract: Pioglitazone inhibited cardiomyocyte apoptosis and reduced mitochondrial ultrastructure injury and membrane potential loss in the ischemic/reperfused heart of rat. These protective effects of pioglitazone may be related to opening mitochondrial(ATP)-sensitive potassium channels.

Cited by 34 publications

References 36 publications

Transient hypoxia induces ERK-dependent anti-apoptotic cell survival in endothelial cells

Transient hypoxia induces ERK-dependent anti-apoptotic cell survival in endothelial cells

Pretreatment of Human Mesenchymal Stem Cells with Pioglitazone Improved Efficiency of Cardiomyogenic Transdifferentiation and Cardiac Function

Use of pioglitazone in the treatment of diabetes: effect on cardiovascular risk

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