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Background <p>Inhibition of hypoxia-induced apoptosis in cardiomyocytes is crucial for heart failure treatment. Previous research suggests that nuclear respiratory factor-1 (NRF-1) protects hypoxic cardiomyocytes against apoptosis. In the present study, we hypothesized that NRF-1 regulates the expression of Caspase 8 and FADD-like apoptosis regulator (CFLAR) and thus contributes to the regulation of apoptosis in hypoxic cardiomyocytes.</p> Methods and results <p>Chromatin immunoprecipitation (ChIP) and Dual-Glo luciferase assays confirmed that NRF-1 binds to the <i>Cflar</i> gene promoter and regulates its transcriptional activity. Furthermore, the interactions between NRF-1 and CFLAR and their effects on H9C2 cardiomyocytes apoptosis were tested under hypoxic conditions. Using the BioTek imaging system, we showed that CFLAR siRNA reversed the effects of NRF-1 overexpression on cell growth and death; CFLAR siRNA markedly increased the apoptosis rates and the activities of Caspase-3 and Caspase-8 in NRF-1-overexpressing cells. Conversely, in NRF-1-knockdown cells, CFLAR overexpression suppressed hypoxia-induced apoptosis. Western blot analysis showed that NRF-1-mediated regulation of CFLAR expression primarily influences the protein levels of cleaved Caspase-8 and tBid, without any significant differences in Bid, Bcl-2, and Bax expression.</p> Conclusions <p>We demonstrated that NRF-1 directly regulates CFLAR expression, thereby inhibiting the death receptor pathway, and ultimately, protects H9C2 cardiomyocytes from hypoxia-induced apoptosis. Our findings will provide novel insights into the molecular mechanisms underlying the protective role of NRF-1 and support its potential to serve as a therapeutic target for ameliorating heart failure.</p>

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Nuclear respiratory factor-1 promotes CFLAR transcription in H9C2 cardiomyocytes, protecting them against hypoxia-induced apoptosis

  • 期刊论文

  • 发表日期：

    2025年6月6日

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  • Hui Li,
  • Yunxia Ma,
  • Junliang Li,
  • Siyu Hou,
  • Hui Song,
  • Yazhou Zhu,
  • Wei Zhao

摘要

Background

Inhibition of hypoxia-induced apoptosis in cardiomyocytes is crucial for heart failure treatment. Previous research suggests that nuclear respiratory factor-1 (NRF-1) protects hypoxic cardiomyocytes against apoptosis. In the present study, we hypothesized that NRF-1 regulates the expression of Caspase 8 and FADD-like apoptosis regulator (CFLAR) and thus contributes to the regulation of apoptosis in hypoxic cardiomyocytes.

Methods and results

Chromatin immunoprecipitation (ChIP) and Dual-Glo luciferase assays confirmed that NRF-1 binds to the Cflar gene promoter and regulates its transcriptional activity. Furthermore, the interactions between NRF-1 and CFLAR and their effects on H9C2 cardiomyocytes apoptosis were tested under hypoxic conditions. Using the BioTek imaging system, we showed that CFLAR siRNA reversed the effects of NRF-1 overexpression on cell growth and death; CFLAR siRNA markedly increased the apoptosis rates and the activities of Caspase-3 and Caspase-8 in NRF-1-overexpressing cells. Conversely, in NRF-1-knockdown cells, CFLAR overexpression suppressed hypoxia-induced apoptosis. Western blot analysis showed that NRF-1-mediated regulation of CFLAR expression primarily influences the protein levels of cleaved Caspase-8 and tBid, without any significant differences in Bid, Bcl-2, and Bax expression.

Conclusions

We demonstrated that NRF-1 directly regulates CFLAR expression, thereby inhibiting the death receptor pathway, and ultimately, protects H9C2 cardiomyocytes from hypoxia-induced apoptosis. Our findings will provide novel insights into the molecular mechanisms underlying the protective role of NRF-1 and support its potential to serve as a therapeutic target for ameliorating heart failure.