E4BP4 inhibits AngII-induced apoptosis in H9c2 cardiomyoblasts by activating the PI3K-Akt pathway and promoting calcium uptake

Chen, Bih Cheng; Shibu, Marthandam Asokan; Kuo, Chia‐Hua; Shen, Chia Yao; Chang-Lee, Shu Nu; Lai, Chao Hung; Chen, Ray Jade; Yao, Chun Hsu; Viswanadha, Vijaya Padma; Liu, Jian Shen; Chen, Wei Kung; Huang, Chih‐Yang

doi:10.1016/j.yexcr.2018.01.012

Cited by 8 publications

(6 citation statements)

References 64 publications

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“…This is caused by a decrease in PARP1 ubiquitination mediated by the proteasome after Sirt2 knockout, which is consistent with our previous research. 25 The caspase3 precursor also increased after Ang II induction, in line with previous research, 34 but the level of caspase3 was not affected by SIRT2.…”

Section: Resultssupporting

confidence: 89%

Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy

Zhang

Zou

et al. 2023

Circulation Research

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Background: Hypertension can lead to podocyte damage and subsequent apoptosis, eventually resulting in glomerulosclerosis. Although alleviating podocyte apoptosis has clinical significance for the treatment of hypertensive nephropathy, an effective therapeutic target has not yet been identified. The function of septin4, a proapoptotic protein and an important marker of organ damage, is regulated by post-translational modification. However, the exact role of septin4 in regulating podocyte apoptosis and its connection to hypertensive renal damage remains unclear. Methods: We investigated the function and mechanism of septin4 in hypertensive nephropathy to discover a theoretical basis for targeted treatment. Mouse models including Rosa26-Sirt2 (silent mating type information regulation 2 homolog-2)-Flag mice, SIRT2-knockout, and septin4-K174Q mutant mice, combined with proteomic and acetyl proteomics analysis, followed by multiple molecular biological methodologies, were used to demonstrate mechanisms of SIRT2-mediated deacetylation of septin4-K174 in hypertensive nephropathy. Results: Using transgenic septin4-K174Q mutant mice treated with the antioxidant Tempol, we found that hyperacetylation of the K174 site of septin4 exacerbates Ang II (angiotensin II)– induced hypertensive renal injury resulting from oxidative stress. Proteomics and Western blotting assays indicated that septin4-K174Q activates the cleaved-PARP1 (poly [ADP-ribose] polymerase family, member 1)-cleaved-caspase3 pathway. In septin4-knockdown human renal podocytes, septin4-K174R, which mimics deacetylation at K174, rescues podocyte apoptosis induced by Ang II. Immunoprecipitation and mass spectrometry analyses identified SIRT2 as a deacetylase that interacts with the septin4 GTPase domain and deacetylates septin4-K174. In Sirt2-deficient mice and SIRT2-knockdown renal podocytes, septin4-K174 remains hyperacetylated and exacerbates hypertensive renal injury. By contrast, in Rosa26-Sirt2-Flag (SIRT2-TG) mice and SIRT2-knockdown renal podocytes reexpressing wild-type SIRT2, septin4-K174 is hypoacetylated and mitigates hypertensive renal injury. Conclusions: Septin4, when activated through acetylation of K174 (K174Q), promotes hypertensive renal injury. Septin4-K174R, which mimics deacetylation by SIRT2, inhibits the cleaved-PARP1-cleaved-caspase3 pathway. Septin4-K174R acts as a renal protective factor, mitigating Ang II–induced hypertensive renal injury. These findings indicate that septin4-K174 is a potential therapeutic target for the treatment of hypertensive renal injury.

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Section: Resultssupporting

confidence: 89%

Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy

Zhang

Zou

et al. 2023

Circulation Research

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“…The potential transcription repression effect of E4BP4 on the IGF-2 expression was investigated. Study outcomes showed that E4BP4 effectively suppresses the transcriptional levels of IGF-2 and established its cardioprotective effects against Ang II-induced apoptosis by inhibiting IGF-II transcription and by regulating Ca 2+ signaling (Chen et al, 2018). Both E4BP4 and IGF-1 are known to be overexpressed in a diseased heart and are known to assume antiapoptotic or antiinflammatory effects in the course of heart disease progression (Weng et al, 2010).…”

Section: Insulin-like Growth Factor II Receptor (Igf2r) Signalingmentioning

confidence: 99%

“…The lack of imprinted IGF2R has resulted in ventricular hyperplasia in a transgenic model of mice (Lau et al, ). In fact, reduced expression levels of IGF2R have been correlated with cell proliferation, diminished hypoxia and tumor necrosis factor (IGF)‐induced apoptosis in neonatal cardiac myocytes of rats (R. J. Chen et al, ). The expression of IGF2R has been induced by the ligation of abdominal aorta and apoptosis in heart.…”

Section: Pathways Regulated By E4bp4mentioning

confidence: 99%

A minireview of E4BP4/NFIL3 in heart failure

Velmurugan

Chang

Shibu

et al. 2018

Journal Cellular Physiology

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Heart failure (HF) remains a major cause of morbidity and mortality worldwide. The primary cause identified for HF is impaired left ventricular myocardial function, and clinical manifestations may lead to severe conditions like pulmonary congestion, splanchnic congestion, and peripheral edema. Development of new therapeutic strategies remains the need of the hour for controlling the problem of HF worldwide. Deeper insights into the molecular mechanisms involved in etiopathology of HF indicate the significant role of calcium signaling, autocrine signaling pathways, and insulin-like growth factor-1 signaling that regulates the physiologic functions of heart growth and development such as contraction, metabolism, hypertrophy, cytokine signaling, and apoptosis. In view of these facts, a transcription factor (TF) regulating the myriad of these signaling pathways may prove as a lead candidate for development of therapeutics. Adenovirus E4 promoter-binding protein (E4BP4), also known as nuclear-factor, interleukin 3 regulated (NFIL3), a type of basic leucine zipper TF, is known to regulate the signaling processes involved in the functioning of heart. The current review discusses about the expression, structure, and functional role of E4BP4 in signaling processes with emphasis on calcium signaling mechanisms, autocrine signaling, and insulin-like growth factor II receptor-mediated processes regulated by E4BP4 that may regulate the pathogenesis of HF. We propose that E4BP4, being the critical component for the regulation of the above signaling processes, may serve as a novel therapeutic target for HF, and scientific investigations are merited in this direction.

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“…It was identified that NFIL3 could bind to the promoter of IL-3 and serve as a transcriptional activator of IL-3. [36][37][38] Moreover, NFIL3 attenuated proinflammatory cytokines IL-5, IL-12, and IL-13 production, while augmented the expression of anti-inflammatory cytokine IL-10. 35 NFIL3 plays the role of a survival mediator in heart; overexpression of NFIL3 promotes cell survival and blocks apoptosis in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 94%

“…A previous report indicated that NFIL3 played a central role in cardiovascular disease and regulated the pathogenesis of heart failure . NFIL3 plays the role of a survival mediator in heart; overexpression of NFIL3 promotes cell survival and blocks apoptosis in cardiomyocytes . Moreover, NFIL3 attenuated proinflammatory cytokines IL‐5, IL‐12, and IL‐13 production, while augmented the expression of anti‐inflammatory cytokine IL‐10 .…”

Section: Discussionmentioning

confidence: 96%

miR‐203 accelerates apoptosis and inflammation induced by LPS via targeting NFIL3 in cardiomyocytes

Liu

et al. 2018

J of Cellular Biochemistry

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Myocarditis is an inflammatory disease of the myocardium. MicroRNA‐203 (miR‐203) is involved in various physiological and pathological processes. In this work, we aimed to explore the roles and potential mechanisms of miR‐203 in myocarditis in vitro. Cardiomyocyte H9c2 was subjected to 10 μg/mL lipopolysaccharide (LPS) for 24 hours. Real‐time polymerase chain reaction analysis revealed that LPS upregulated miR‐203 expression in H9c2 cells. Cell counting kit‐8 (CCK‐8) and lactate dehydrogenase (LDH) assays demonstrated that inhibition of miR‐203 reduced cell injury induced by LPS. The cell apoptosis rate, caspase 3 activity, caspase 3/7 activities, and the expression of cleaved‐caspase 3 (c‐caspase 3) were declined upon miR‐203 depletion. In addition, miR‐203 silencing attenuated the expression and production of inflammatory cytokines (tumor necrosis factor‐α, interleukin [IL]‐6, and IL‐8). On the contrary, overexpression of miR‐203 showed the opposite trend in cell apoptosis and inflammation. Luciferase reporter assay confirmed that miR‐203 could bind with the nuclear factor interleukin‐3 (NFIL3) 3′‐untranslated regions (3′‐UTR), and miR‐203 regulated the expression of NFIL3 negatively. Moreover, NFIL3 silencing partly abolished the myocardial protective functions of miR‐203 inhibitor. Herein, we suggest that miR‐203 promoted cell apoptosis and inflammation induced by LPS via targeting NFIL3.

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E4BP4 inhibits AngII-induced apoptosis in H9c2 cardiomyoblasts by activating the PI3K-Akt pathway and promoting calcium uptake

Cited by 8 publications

References 64 publications

Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy

Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy

A minireview of E4BP4/NFIL3 in heart failure

miR‐203 accelerates apoptosis and inflammation induced by LPS via targeting NFIL3 in cardiomyocytes

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