Hypoxia suppresses myocardial survival pathway through HIF-1α-IGFBP-3-dependent signaling and enhances cardiomyocyte autophagic and apoptotic effects mainly via FoxO3a-induced BNIP3 expression

Feng, Chih Chung; Lin, Chien Chung; Lai, Yi Ping; Chen, Tung-Sheng; Shibu, Marthandam Asokan; Lin, Jing Ying; Lin, Kuan Ho; Viswanadha, Vijaya Padma; Kuo, Wei Wen; Huang, Chih Yang

doi:10.1080/08977194.2016.1191480

Cited by 46 publications

(52 citation statements)

References 46 publications

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“…We found that high glucose plus hypoxia enhanced the nuclear translocation of HIF‐1α and FoxO3a. This is consistent with our previous study, where we showed that prolonged hypoxia promoted not only HIF‐1α but also FoxO3a nuclear translocation (Feng et al, ). Third, we found that inhibition of HIF‐1α using inhibitor significantly suppressed BNIP3 expression under hypoxia plus high glucose condition, which was correlated with HIF‐1α expression (Figure a).…”

Section: Discussionsupporting

confidence: 94%

“…It has been known that hypoxia and acidosis activate cardiac myocyte death through the Bcl‐2 family protein BNIP3 (Kubasiak, Hernandez, Bishopric, & Webster, ). We previously demonstrated that hypoxia suppressed myocardial cell survival through HIF‐1α—IGFBP‐3‐dependent signaling pathway and enhanced cardiomyocyte autophagic and apoptotic effects mainly via FoxO3a‐induced BNIP3 expression (Feng et al, ). This study focused on whether HIF‐1α, FoxO3a, and BNIP3 were also involved in hypoxic heart under elevated glucose levels.…”

Section: Discussionmentioning

confidence: 99%

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Synergistic effect of HIF‐1α and FoxO3a trigger cardiomyocyte apoptosis under hyperglycemic ischemia condition

Chen

Pandey

Day

et al. 2017

Journal Cellular Physiology

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Cardiomyocyte death is an important pathogenic feature of ischemia and heart failure. Through this study, we showed the synergistic role of HIF-1α and FoxO3a in cardiomyocyte apoptosis subjected to hypoxia plus elevated glucose levels. Using gene specific small interfering RNAs (siRNA), semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR), Western blot, immunofluorescence, nuclear and cytosolic localization and TUNEL assay techniques, we determined that combined function of HIF-1α and FoxO3a under high glucose plus hypoxia condition lead to enhanced expression of BNIP3 inducing cardiomyocyte death. Our results highlighted the importance of the synergistic role of HIF-1α and FoxO3a in cardiomyocyte death which may add insight into therapeutic approaches to pathophysiology associated with ischemic diabetic cardiomyopathies.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Synergistic effect of HIF‐1α and FoxO3a trigger cardiomyocyte apoptosis under hyperglycemic ischemia condition

Chen

Pandey

Day

et al. 2017

Journal Cellular Physiology

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“…Although previous investigations have reported that HIF-1α or FOXO3 are involved in BNIP3 expression under hypoxia [33], [34], their roles in BNIP3 expression seem to vary with cell type [35], [36], [37]. To demonstrate the detailed mechanism regulating BNIP3 expression in UCB-hMSCs under hypoxia, we investigated the roles of HIF-1α and FOXO3 in BNIP3 regulation.…”

Section: Resultsmentioning

confidence: 97%

BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid production enhancing therapeutic potential of umbilical cord blood-derived human mesenchymal stem cells

et al. 2017

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Mitophagy under hypoxia is an important factor for maintaining and regulating stem cell functions. We previously demonstrated that fatty acid synthase (FASN) induced by hypoxia is a critical lipid metabolic factor determining the therapeutic efficacy of umbilical cord blood-derived human mesenchymal stem cells (UCB-hMSCs). Therefore, we investigated the mechanism of a major mitophagy regulator controlling lipid metabolism and therapeutic potential of UCB-hMSCs. This study revealed that Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-dependent mitophagy is important for reducing mitochondrial reactive oxygen species accumulation, anti-apoptosis, and migration under hypoxia. And, BNIP3 expression was regulated by CREB binding protein-mediated transcriptional actions of HIF-1α and FOXO3. Silencing of BNIP3 suppressed free fatty acid (FFA) synthesis regulated by SREBP1/FASN pathway, which is involved in UCB-hMSC apoptosis via caspases cleavage and migration via cofilin-1-mediated F-actin reorganization in hypoxia. Moreover, reduced mouse skin wound-healing capacity of UCB-hMSC with hypoxia pretreatment by BNIP3 silencing was recovered by palmitic acid. Collectively, our findings suggest that BNIP3-mediated mitophagy under hypoxia leads to FASN-induced FFA synthesis, which is critical for therapeutic potential of UCB-hMSCs with hypoxia pretreatment.

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“…BNIP3 then forms a stable homodimer complex that is inserted into the mitochondrial membrane, causing mitochondrial damage and triggering mitochondrion-dependent apoptosis [6]. Earlier reports suggested that BNIP3 plays a pivotal role in the loss of skeletal muscle mass and provides a potential therapeutic target in muscle wasting disorders and other diseases that involve autophagy [7].…”

Section: Introductionmentioning

confidence: 99%

Effects of Cobalt Chloride, a Hypoxia-Mimetic Agent, on Autophagy and Atrophy in Skeletal C2C12 Myotubes

Chen

Jiang

She

et al. 2017

BioMed Research International

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Background Hypoxia-induced autophagy and muscle wasting occur in several environmental and pathological conditions. However, the molecular mechanisms underlying the effects of the hypoxia-mimetic agent CoCl2 on autophagy and muscle atrophy are still unclear. Methods C2C12 myotubes were exposed to increasing concentrations of CoCl2 for 24 hours. Quantitative RT-PCR, Western blotting, and transmission electron microscopy were performed to confirm autophagy occurs. Autophagy proteins were measured to understand the molecule mechanisms. We also inhibited hypoxic autophagy and examined the changes in myogenin expression, myotubes formation, and apoptosis. Results Our results showed that CoCl2-mimicked hypoxia upregulated the expression of the autophagy-related proteins LC3, HIF-1α, BNIP3, p-AMPKα, and beclin-1, whereas p62 and p-mTOR were downregulated. In addition, the autophagosome could be observed after CoCl2 induction. The expression of the autophagy-related E3 ligase parkin and the muscle-specific ubiquitin ligase atrogin-1 was increased by CoCl2. Inhibition of autophagy by 3MA increased myogenin expression and promoted myotubes formation and the percentage of cell death was decreased. Conclusions Our results confirmed that CoCl2-mimicked hypoxia induced autophagy via the HIF-1α/BNIP3/beclin-1 and AMPK/mTOR pathways. Our results also revealed an important link between autophagy and muscle atrophy under hypoxia, which may help to develop new therapeutic strategies for muscle diseases.

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Hypoxia suppresses myocardial survival pathway through HIF-1α-IGFBP-3-dependent signaling and enhances cardiomyocyte autophagic and apoptotic effects mainly via FoxO3a-induced BNIP3 expression

Cited by 46 publications

References 46 publications

Synergistic effect of HIF‐1α and FoxO3a trigger cardiomyocyte apoptosis under hyperglycemic ischemia condition

Synergistic effect of HIF‐1α and FoxO3a trigger cardiomyocyte apoptosis under hyperglycemic ischemia condition

BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid production enhancing therapeutic potential of umbilical cord blood-derived human mesenchymal stem cells

Effects of Cobalt Chloride, a Hypoxia-Mimetic Agent, on Autophagy and Atrophy in Skeletal C2C12 Myotubes

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