PTEN signaling inhibitor VO-OHpic improves cardiac myocyte survival by mediating apoptosis resistance in vitro

Li, Zhang; Cheng, Zhenfeng; Yu, Haifeng; Chen, Mengting; Li, Lifang

doi:10.1016/j.biopha.2018.04.141

Cited by 10 publications

(9 citation statements)

References 14 publications

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“…Dysregulation of the PTEN/PI3K/AKT signaling pathway is implicated in a number of diseases including cancer, where PTEN mutations and deletions consequently lead to increased cell proliferation and reduced cell death. [80] Our findings complement recent studies in which PTEN partial inhibition, achieved either through small molecules, gene knockdown, or miR-NAs led to increased cardiomyocyte proliferation [81] and reduced apoptosis [82] in vitro, and attenuation of endothelial cell apoptosis [83] and overall improved cardiac outcomes [84] in vivo. The PI3K/AKT pathway also mediates other prosurvival mechanisms unexplored in this work, namely inhibition of pro-apoptotic proteins, such as BAD, [85] and inhibition of pro-apoptotic signals generated by transcription factors like FOXO1.…”

Section: Discussionsupporting

confidence: 85%

Bioactivity and miRNome Profiling of Native Extracellular Vesicles in Human Induced Pluripotent Stem Cell‐Cardiomyocyte Differentiation

et al. 2022

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Extracellular vesicles (EV) are an attractive therapy to boost cardiac regeneration. Nevertheless, identification of native EV and corresponding cell platform(s) suitable for therapeutic application, is still a challenge. Here, EV are isolated from key stages of the human induced pluripotent stem cell-cardiomyocyte (hiPSC-CM) differentiation and maturation, i.e., from hiPSC (hiPSC-EV), cardiac progenitors, immature and mature cardiomyocytes, with the aim of identifying a promising cell biofactory for EV production, and pinpoint the genetic signatures of bioactive EV. EV secreted by hiPSC and cardiac derivatives show a typical size distribution profile and the expression of specific EV markers. Bioactivity assays show increased tube formation and migration in HUVEC treated with hiPSC-EV compared to EV from committed cell populations. hiPSC-EV also significantly increase cell cycle activity of hiPSC-CM. Global miRNA expression profiles, obtained by small RNA-seq analysis, corroborate an EV-miRNA pattern indicative of stem cell to cardiomyocyte specification, confirming that hiPSC-EV are enriched in pluripotency-associated miRNA with higher in vitro pro-angiogenic and pro-proliferative properties. In particular, a stemness maintenance miRNA cluster upregulated in hiPSC-EV targets the PTEN/PI3K/AKT pathway, involved in cell proliferation and survival. Overall, the findings validate hiPSC as cell biofactories for EV production for cardiac regenerative applications.

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Section: Discussionsupporting

confidence: 85%

Bioactivity and miRNome Profiling of Native Extracellular Vesicles in Human Induced Pluripotent Stem Cell‐Cardiomyocyte Differentiation

et al. 2022

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“…PTEN mutation is the most common mutation in tumor suppressor genes which may negatively regulate cell function [29][30][31]. It has been universally acknowledged that the most important role of PTEN is to regulate growth and development, including cell growth, adhesion, migration, invasion, and apoptosis, and it also serves as the key regulator of pathogenesis in a variety of cardiovascular diseases (CVD), probably via the PI3K/Akt signaling pathway [32][33][34][35][36]. Multiple physical and chemical stimuli can activate PI3K and thereby phosphorylate-Akt (p-Akt), which subsequently functions as a key factor in downstream effectors [37,38].…”

Section: Discussionmentioning

confidence: 99%

Levosimendan Protects against Doxorubicin-Induced Cardiotoxicity by Regulating the PTEN/Akt Pathway

Zhang

et al. 2020

BioMed Research International

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Background and Aims. Myocyte apoptosis plays a critical role in the development of doxorubicin- (DOX-) induced cardiotoxicity. In addition to its cardiotonic effect, laboratory evidence indicates that levosimendan can inhibit apoptosis, but its role in DOX-induced cardiac injury remains unclear. Therefore, the present study is aimed at exploring whether levosimendan could attenuate DOX-induced cardiotoxicity. Methods. Levosimendan (1 mg/kg) was administered to mice through oral gavage once daily for 4 weeks, and the mice were also subjected to an intraperitoneal injection of DOX (5 mg/kg) or saline, once a week for 4 weeks, to create a chronic model of DOX-induced cardiotoxicity. A morphological examination and biochemical analysis were used to evaluate the effects of levosimendan. H9C2 cells were used to verify the protective role of levosimendan in vitro. And an Akt inhibitor was utilized to verify the cardioprotection of levosimendan. Results. Levosimendan reduced the cardiac dysfunction and attenuated the myocardial apoptosis induced by DOX in vivo and in vitro. Levosimendan also inhibited the activation of phosphatase and tensin homolog (PTEN) and upregulated P-Akt expression both in vivo and in vitro. And inhibition of Akt abolished the cardioprotection of levosimendan in vitro. Conclusion. Levosimendan may protect against DOX-induced cardiotoxicity via modulation of the PTEN/Akt signaling pathway.

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“…In a sudden cardiac arrest model by Li et al (20), it was shown that VO reduces expression of the proinflammatory cytokines IL-1␤ and TNF-␣ and increases anti-inflammatory IL-10 expression. Additionally, a recent in vitro study showed that VO treatment can reduce apoptosis and promote cardiomyocyte survival (21). These studies suggest VO's potential for therapeutic use in cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 87%

PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy

Johnson

Singla

2018

American Journal of Physiology-Heart and Circulatory Physiology

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Doxorubicin (Doxo) is an effective agent commonly used in cancer therapeutics. Unfortunately, Doxo treatment can stimulate cardiomyopathy and subsequent heart failure, limiting use of this drug. The role of phosphatase and tensin homolog (PTEN) in apoptosis has been documented in Doxo induced cardiomyopathy (DIC) and heart failure models. However, whether direct inhibition of PTEN attenuates apoptosis, cardiac remodeling, and inflammatory M1 macrophages in DIC model remains elusive. Therefore, the current study is designed to understand effects of VO-OHpic (VO), a potent inhibitor of PTEN, in reducing apoptosis and cardiac remodeling. At D56, echocardiography was performed, which shows VO-OHpic treatment significantly (p<0.05) improves heart function. Immunohistochemistry, TUNEL, and histological staining were used to determine apoptosis, pro-inflammatory M1 macrophages, anti-inflammatory M2 macrophages, and cardiac remodeling. Our data shows a significant increase in apoptosis, hypertrophy, fibrosis, and pro-inflammatory M1 macrophages with Doxo treatment, whereas VO treatment significantly reduced apoptosis, adverse cardiac remodeling, and pro-inflammatory M1 macrophages significantly (p<0.05) compared to Doxo group. Western blotting confirmed the reduction of p-PTEN and increase in p-AKT protein expression in the Doxo+VO group. Moreover, VO administration increased anti-inflammatory M2 macrophages. Collectively, our data suggests that VO-OHpic treatment attenuates apoptosis and adverse cardiac remodeling, a process that is mediated through PTEN/AKT pathway, resulting in improved heart function in DIC.

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PTEN signaling inhibitor VO-OHpic improves cardiac myocyte survival by mediating apoptosis resistance in vitro

Cited by 10 publications

References 14 publications

Bioactivity and miRNome Profiling of Native Extracellular Vesicles in Human Induced Pluripotent Stem Cell‐Cardiomyocyte Differentiation

Bioactivity and miRNome Profiling of Native Extracellular Vesicles in Human Induced Pluripotent Stem Cell‐Cardiomyocyte Differentiation

Levosimendan Protects against Doxorubicin-Induced Cardiotoxicity by Regulating the PTEN/Akt Pathway

PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy

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