Hypoxic Stress-Dependent Regulation of Na,K-ATPase in Ischemic Heart Disease

Baloglu, Emel

doi:10.3390/ijms24097855

Cited by 5 publications

(9 citation statements)

References 157 publications

(179 reference statements)

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“…Hypoxia (a hallmark feature of IHD) was used to stress hearts from male and female p62icKO mice. 82 In the p62icKO female mice, hypoxia decreased systolic function to a greater degree as compared to normoxia, an effect that was not observed in the male mice ( Figure 1 A and B ).…”

Section: Discussionmentioning

confidence: 82%

Sequestosome 1 (p62) mitigates hypoxia-induced cardiac dysfunction by stabilizing hypoxia-inducible factor 1α and nuclear factor erythroid 2-related factor 2

Ghosh,

Fatahian,

Rouzbehani

et al. 2024

Cardiovascular Research

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Aims Heart failure due to ischaemic heart disease (IHD) is a leading cause of mortality worldwide. A major contributing factor to IHD-induced cardiac damage is hypoxia. Sequestosome 1 (p62) is a multi-functional adaptor protein with pleiotropic roles in autophagy, proteostasis, inflammation, and cancer. Despite abundant expression in cardiomyocytes, the role of p62 in cardiac physiology is not well understood. We hypothesized that cardiomyocyte-specific p62 deletion evokes hypoxia-induced cardiac pathology by impairing hypoxia-inducible factor 1α (Hif-1α) and nuclear factor erythroid 2-related factor 2 (Nrf2) signalling. Methods and results Adult mice with germline deletion of cardiomyocyte p62 exhibited mild cardiac dysfunction under normoxic conditions. Transcriptomic analyses revealed a selective impairment in Nrf2 target genes in the hearts from these mice. Demonstrating the functional importance of this adaptor protein, adult mice with inducible depletion of cardiomyocyte p62 displayed hypoxia-induced contractile dysfunction, oxidative stress, and cell death. Mechanistically, p62-depleted hearts exhibit impaired Hif-1α and Nrf2 transcriptional activity. Because findings from these two murine models suggested a cardioprotective role for p62, mechanisms were evaluated using H9c2 cardiomyoblasts. Loss of p62 in H9c2 cells exposed to hypoxia reduced Hif-1α and Nrf2 protein levels. Further, the lack of p62 decreased Nrf2 protein expression, nuclear translocation, and transcriptional activity. Repressed Nrf2 activity associated with heightened Nrf2-Keap1 co-localization in p62-deficient cells, which was concurrent with increased Nrf2 ubiquitination facilitated by the E3 ligase Cullin 3, followed by proteasomal-mediated degradation. Substantiating our results, a gain of p62 in H9c2 cells stabilized Nrf2 and increased the transcriptional activity of Nrf2 downstream targets. Conclusion Cardiac p62 mitigates hypoxia-induced cardiac dysfunction by stabilizing Hif-1α and Nrf2.

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Section: Discussionmentioning

confidence: 82%

Sequestosome 1 (p62) mitigates hypoxia-induced cardiac dysfunction by stabilizing hypoxia-inducible factor 1α and nuclear factor erythroid 2-related factor 2

Ghosh,

Fatahian,

Rouzbehani

et al. 2024

Cardiovascular Research

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“…The decreased NKA activity has been attributed to decreased expression of the subunit proteins. However, inconsistent findings from expression studies cannot substantially clarify the decreased NKA activity [2]. For instance, in a rabbit heart failure model, Bossuyt et al reported increased intracellular Na + accumulation, decreased NKA activity along with decreased protein expression of α1and α2-NKA in ventricular homogenates and isolated myocytes.…”

Section: Discussionmentioning

confidence: 99%

“…The Na,K-ATPase (NKA) pump is a member of the P-type ATPase family [1]. In the heart muscle it maintains the generation of action potentials, electrical activity, maintenance of Na + and Ca 2+ ion gradients, and cell survival [2]. Thus, proper function of the NKA is vital for cellular viability.…”

Section: Introductionmentioning

confidence: 99%

HIF-2α Controls Expression and Intracellular Trafficking of the α2-Subunit of Na,K-ATPase in Hypoxic H9c2 Cardiomyocytes

Baloglu

2023

Biomedicines

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The Na,K-ATPase (NKA) pump plays essential roles for optimal function of the heart. NKA activity decreases in necropsy materials from ischemic heart disease, heart failure and in experimental models. Cellular adaptation to hypoxia is regulated by hypoxia-induced transcription factors (HIF); we tested whether HIFs are involved in regulating the expression and intracellular dynamics of the α2-isoform of NKA (α2-NKA). HIF-1α and HIF-2α expression was suppressed in H9c2 cardiomyocytes by adenoviral infection, where cells were kept in 1% O2 for 24 h. The silencing efficiency of HIFs was tested on the mRNA and protein expression. We measured the mRNA expression of α2-NKA in HIF-silenced and hypoxia-exposed cells. The membrane and intracellular expression of α2-NKA was measured after labelling the cell surface with NHS-SS-biotin, immunoprecipitation and Western blotting. Hypoxia increased the mRNA expression of α2-NKA 5-fold compared to normoxic cells in an HIF-2α-sensitive manner. The plasma membrane expression of α2-NKA increased in hypoxia by 2-fold and was fully prevented by HIF-2α silencing. Intracellular expression of α2-NKA was not affected. These results showed for the first time that in hypoxic cardiomyocytes α2-NKA is transcriptionally and translationally regulated by HIF-2α. The molecular mechanism behind this regulation needs further investigation.

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“…There is also an increase in anaerobic glycolysis that generates lactate and causes a change in intracellular pH that drops to a value of 6.2 after about ten minutes [153]. An ionic imbalance is therefore established also due to the blockage of the Na + /K + and Na + /Ca 2+ pumps; Na + and Ca 2+ accumulate inside the cell which, combined with the accumulation of other metabolites such as lactate and protons, draws water inside the cell, causing swelling [154,155]. Reperfusion provides oxygen and allows the replenishment of substrates in the ischemic area that are essential to produce ATP, glucose, and fatty acids, all of which are important for cell survival but can also contribute to exacerbating ischemic damage.…”

Section: Ischemic Reperfusion Injurymentioning

confidence: 99%

Ferroptosis: Emerging Role in Diseases and Potential Implication of Bioactive Compounds

Patanè,

Putaggio,

Tellone

et al. 2023

IJMS

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Ferroptosis is a form of cell death that is distinguished from other types of death for its peculiar characteristics of death regulated by iron accumulation, increase in ROS, and lipid peroxidation. In the past few years, experimental evidence has correlated ferroptosis with various pathological processes including neurodegenerative and cardiovascular diseases. Ferroptosis also is involved in several types of cancer because it has been shown to induce tumor cell death. In particular, the pharmacological induction of ferroptosis, contributing to the inhibition of the proliferative process, provides new ideas for the pharmacological treatment of cancer. Emerging evidence suggests that certain mechanisms including the Xc− system, GPx4, and iron chelators play a key role in the regulation of ferroptosis and can be used to block the progression of many diseases. This review summarizes current knowledge on the mechanism of ferroptosis and the latest advances in its multiple regulatory pathways, underlining ferroptosis’ involvement in the diseases. Finally, we focused on several types of ferroptosis inducers and inhibitors, evaluating their impact on the cell death principal targets to provide new perspectives in the treatment of the diseases and a potential pharmacological development of new clinical therapies.

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Hypoxic Stress-Dependent Regulation of Na,K-ATPase in Ischemic Heart Disease

Cited by 5 publications

References 157 publications

Sequestosome 1 (p62) mitigates hypoxia-induced cardiac dysfunction by stabilizing hypoxia-inducible factor 1α and nuclear factor erythroid 2-related factor 2

Sequestosome 1 (p62) mitigates hypoxia-induced cardiac dysfunction by stabilizing hypoxia-inducible factor 1α and nuclear factor erythroid 2-related factor 2

HIF-2α Controls Expression and Intracellular Trafficking of the α2-Subunit of Na,K-ATPase in Hypoxic H9c2 Cardiomyocytes

Ferroptosis: Emerging Role in Diseases and Potential Implication of Bioactive Compounds

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