Pharmacological inhibition of PTEN limits myocardial infarct size and improves left ventricular function postinfarction

Keyes, Kyle T.; Xu, Jing; Long, Bo; Zhang, Congfang; Hu, Zhaoyong; Ye, Yumei

doi:10.1152/ajpheart.00915.2009

Cited by 89 publications

(87 citation statements)

References 36 publications

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“…Furthermore, bpV(HOpic) has been shown to attenuate simulated ischemia/reperfusion injury in cardiomyocytes, and to limit myocardial infarct size and ameliorate cardiac dysfuction post-infarct in vivo (7). To further investigate the protective effects of other bpVs on cardiomyocytes, we selected bpV(pic) and bpV(phen) from a list of bpV compounds that have already been tested on PTEN (8).…”

Section: Discussionmentioning

confidence: 99%

“…However, few strategies directed against MIRI have been tested under clinical conditions (5,6). Recently, a new finding showed that the pharmacological inhibition of lipid phosphatase and tension homolog on chromosome 10 (PTEN) limited myocardial infarct size and improved left ventricular function post-infarction (7). Moreover, protein tyrosine phosphatase inhibitors and bisperoxovanadium molecules (bpV) inhibited PTEN specifically at low concentrations (8).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, protein tyrosine phosphatase inhibitors and bisperoxovanadium molecules (bpV) inhibited PTEN specifically at low concentrations (8). The protective effects of bpV(HOpic) on myocardial injury in vitro and in vivo have been observed in previous studies (7). However, other bpV molecules have not been studied and compared for their actions against MIRI.…”

Section: Introductionmentioning

confidence: 99%

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Effects of bpV(pic) and bpV(phen) on H9c2 cardiomyoblasts during both hypoxia/reoxygenation and H2O2-induced injuries

2011

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Abstract. Reactive oxygen species (ROS) are involved in myocardial injury. ROS are known to inactivate lipid phosphatase and tension homolog on chromosome 10 (PTEN), an enzyme that increases apoptosis in neonatal cardiomyocytes. BpV(pic) and bpV(phen), two bisperoxovanadium molecules and PTEN inhibitors, may be involved in limiting myocardial infarction. To compare the protective effects of bpV(pic) and bpV(phen) on ROS-induced cardiomyocyte injury and their possible mechanisms, we selected two popular models of hypoxia/reoxygenation (H/R) and H 2 O 2 -induced injury in H9c2 cardiomyoblasts to investigate their effects against injury. We found that pre-treatment with bpV(pic) and bpV(phen) increased the viability and protected the morphology of H9c2 cells under the conditions of H/R and H 2 O 2 by inhibiting LDH release, apoptosis and caspases 3/8/9 activities. However, their respective inhibitory abilities in the two models were different, suggesting that the quantity of ROS from the two models might be different. However, the conflict between ROS and PTEN may affect the action of bpV(pic) and bpV(phen). Taken together, the results demonstrate that bpV(pic) and bpV(phen) have inhibitory effects on oxidative stress-induced cardiomyocyte injury that may be partially modulated by the action of ROS on PTEN. IntroductionMyocardial ischemia/reperfusion injury (MIRI), which may lead to various complications, including myocardial infarction, cardiac contractile dysfunction and arrhythmia (1-4), has become an increasingly common problem in clinics. However, few strategies directed against MIRI have been tested under clinical conditions (5,6). Recently, a new finding showed that the pharmacological inhibition of lipid phosphatase and tension homolog on chromosome 10 (PTEN) limited myocardial infarct size and improved left ventricular function post-infarction (7). Moreover, protein tyrosine phosphatase inhibitors and bisperoxovanadium molecules (bpV) inhibited PTEN specifically at low concentrations (8). The protective effects of bpV(HOpic) on myocardial injury in vitro and in vivo have been observed in previous studies (7). However, other bpV molecules have not been studied and compared for their actions against MIRI.Based on the cellular mechanisms of ischemia/reperfusion injury that have been extensively explored (9-11), reactive oxygen species (ROS) generated with the re-admission of oxygen are considered the first and main cause of ischemia/ reperfusion injury (12). Thus, scavenging excessive ROS and restoring the reduction-oxidation (redox) balance in the body is an important strategy in inhibiting reperfusion injury, as the redox balance is the solid physiological condition in humans from birth (13,14), and, despite evolution, this balance has always been conserved in all organisms (15,16).Hydrogen dioxide (H 2 O 2 ), a famous ROS, inhibits the lipid phosphatase activity of the tumour suppressor PTEN enzyme (17), which suggests that when produced under pathological conditions, such as during MIRI or chronic inflamm...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of bpV(pic) and bpV(phen) on H9c2 cardiomyoblasts during both hypoxia/reoxygenation and H2O2-induced injuries

2011

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“…However, its role in regulating PTEN during hypoxia or ischemia has not been reported. Here, we also assessed the role of p38 and its downstream mediator activating transcription factor 2 (ATF-2) in upregulation of PTEN in response to prolonged hypoxia in vitro.Despite the fact that PTEN is an attractive target for myocardial protection, only a few studies assessing the role of PTEN inhibition in ischemia-reperfusion or hypoxia models have been published (18,41,46). The difficulty in investigating this phosphatase relates to the lack of highly specific activators or inhibitors.…”

mentioning

confidence: 99%

“…Despite the fact that PTEN is an attractive target for myocardial protection, only a few studies assessing the role of PTEN inhibition in ischemia-reperfusion or hypoxia models have been published (18,41,46). The difficulty in investigating this phosphatase relates to the lack of highly specific activators or inhibitors.…”

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confidence: 99%

Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia

Qian

Ling

Castillo

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Phosphatase and tensin homolog on chromosome 10 (PTEN) is downregulated during hypertrophic and cancerous cell growth, leading to activation of the prosurvival Akt pathway. However, PTEN regulation in cardiac myocytes upon exposure to hypoxia remains unclear. We explored the role of PTEN in response to hypoxia/ischemia in the myocardium. We validated that PTEN is a transcriptional target of activating transcription factor 2 (ATF-2) and is positively regulated via a p38/ATF-2 signaling pathway. Accordingly, hypoxia-induced upregulation of phosphorylation of ATF-2 and PTEN were reversed by a dominant negative mutant p38. Inhibition of PTEN in cardiomyocytes attenuated hypoxiainduced cell death and apoptosis. Cardiac-specific knockout of PTEN resulted in increased phosphorylation of Akt and forkhead box O 1 (forkhead transcription factors), limited infarct size in animals exposed to ischemia-reperfusion injury, and ameliorated deterioration of left ventricular function and remodeling following permanent coronary artery occlusion. In addition, the activation of Bim, FASL, and caspase was coupled with PTEN activation, all of which were attenuated by PTEN inhibition. In conclusion, cardiomyocyte-specific conditional PTEN deletion limited myocardial infarct size in an in vivo model of ischemia-reperfusion injury and attenuated adverse remodeling in a model of chronic permanent coronary artery ligation. p38; activating transcription factor 2; Akt; forkhead box O 1; FAS ligand; ischemia; infarct size; reperfusion PHOSPHOINOSITIDE 3-KINASE (PI3K) phosphorylates phosphatidylinositol, producing phosphatidylinositol (3,4,5)-triphosphate (PIP3), which recruits and facilitates activation of Akt (14, 32). Phosphatase and tensin homolog on chromosome 10 (PTEN) is a dual protein-lipid phosphatase that degrades PIP3 to inactive phosphatidylinositol (4,5)-diphosphate (PIP2; Refs. 22,26,38,47) and so negatively regulates the PI3K/Akt prosurvival signaling pathway. Loss or mutation of PTEN, with subsequent uncontrolled activation of the prosurvival pathways, is common in many tumors, including endometrial carcinoma, melanoma, renal, breast, prostate, and lung cancer (6, 9, 23). Dysregulation of PTEN has also been reported in heart diseases such as cardiac hypotrophy, heart failure, and ischemic heart disease (37,46,55,58). We (18) have shown that pharmacological inhibition of PTEN protects the heart against ischemiareperfusion injury through upregulation of the PI3K/Akt/endothelial nitric oxide synthase/ERK prosurvival pathway. Overexpression of PTEN increases apoptosis in neonatal cardiomyocytes, whereas expression of inactive mutant PTEN leads to Akt activation and reduces apoptosis (42). Moreover, myocardial levels of PTEN are increased in diabetic rats compared with nondiabetic rats, leading to reduced ability to phosphorylate Akt and, hence, blunting the protective effects of ischemic preconditioning (31, 52). Only two studies (41, 46) have assessed the effect of genetic deletion of PTEN on myocardial infarct size, both in an is...

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CD24 blunts the sensitivity of retinoblastoma to vincristine by modulating autophagy

Sun

Feng

et al. 2020

Molecular Oncology

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Retinoblastoma (RB) is the most common childhood malignant intraocular tumor. The clinical efficacy of vincristine (VCR) in the treatment of RB is severely limited by drug resistance. Here, we found that CD24, a GPI-anchored protein, was overexpressed in human RB tissues and RB cell lines, and was associated with the sensitivity of RB cells in response to VCR therapy. We demonstrated that CD24 plays a critical role in impairing RB sensitivity to VCR via regulating autophagy. Mechanistically, CD24 recruits PTEN to the lipid raft domain and regulates the PTEN/AKT/ mTORC1 pathway to activate autophagy. Lipid raft localization was essential for CD24 recruitment function. Collectively, our findings revealed a novel role of CD24 in regulating RB sensitivity to VCR and showed that CD24 is a potential target for improving chemotherapeutic sensitivity and RB patient outcomes. Shields, 2004). The treatment of RB is multimodal. Basic treatment methods are chemotherapy, radiation therapy, enucleation, and focal treatment including transpupillary thermotherapy, cryotherapy, and laser photocoagulation, all playing a vital role (Yanik et al., 2015). Recently, chemotherapy has become the most

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Pharmacological inhibition of PTEN limits myocardial infarct size and improves left ventricular function postinfarction

Cited by 89 publications

References 36 publications

Effects of bpV(pic) and bpV(phen) on H9c2 cardiomyoblasts during both hypoxia/reoxygenation and H2O2-induced injuries

Effects of bpV(pic) and bpV(phen) on H9c2 cardiomyoblasts during both hypoxia/reoxygenation and H2O2-induced injuries

Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia

CD24 blunts the sensitivity of retinoblastoma to vincristine by modulating autophagy

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