GCN2 deficiency ameliorates cardiac dysfunction in diabetic mice by reducing lipotoxicity and oxidative stress

Feng, Wei; Tong, Lei; Wang, Yue; Feng, Run; Yuan, Jun-Tao; Shen, Xiyue; Wu, Yongguang; Gao, Junling; Ding, Wenjun; Lu, Zhigang

doi:10.1016/j.freeradbiomed.2018.10.445

Cited by 38 publications

(39 citation statements)

References 57 publications

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“…Previous reports have shown that oxidative stress may be cell toxic for cardiac myocytes . DCFH‐DA fluorescence probe was performed to measure ROS of different groups in vitro.…”

Section: Resultsmentioning

confidence: 99%

“…Under some conditions, LKB1 is phosphorylated at Ser428 (pLKB1) and then translocated to the cytosol and subsequently induces activation of AMPK . Although several lines of evidence demonstrate that AMPK phosphorylation is attenuated in diet‐induced obesity (DIO) mouse hearts, the mechanisms by which AMPK phosphorylation is decreased are not fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high‐fat diet‐induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway

Zuo

Zhao

et al. 2020

J Cellular Molecular Medi

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CTRP9 has been reported to regulate lipid metabolism and exert cardioprotective effects, yet its role in high‐fat diet (HFD)‐induced cardiac lipotoxicity and the underlying mechanisms remain unclear. In the current study, we established HFD‐induced obesity model in wild‐type (WT) or CTRP9 knockout (CTRP9‐KO) mice and palmitate‐induced lipotoxicity model in neonatal rat cardiac myocytes (NRCMs) to investigate the effects of CTRP9 on cardiac lipotoxicity. Our results demonstrated that the HFD‐fed CTRP9‐KO mice accentuated cardiac hypertrophy, fibrosis, endoplasmic reticulum (ER) stress‐initiated apoptosis and oxidative stress compared with the HFD‐fed WT mice. In vitro, CTRP9 treatment markedly alleviated palmitate‐induced oxidative stress and ER stress‐induced apoptosis in NRCMs in a dose‐dependent manner. Phosphorylated AMPK at Thr172 was reduced, and phosphorylated mammalian target of rapamycin (mTOR) was strengthened in the heart of the HFD‐fed CTRP9‐KO mice compared with the HFD‐fed control mice. In vitro, AMPK inhibitor compound C significantly abolished the effects of CTRP9 on the inhibition of the apoptotic pathway in palmitate‐treated NRCMs. In a further mechanistic study, CTRP9 enhanced expression of phosphorylated LKB1 at Ser428 and promoted LKB1 cytoplasmic localization. Besides, silencing of LKB1 gene by lentivirus significantly prohibited activation of AMPK by CTRP9 and partially eliminated the protective effect of CTRP9 on the cardiac lipotoxicity. These results indicate that CTRP9 exerted anti‐myocardial lipotoxicity properties and inhibited cardiac hypertrophy probably through the LKB1/AMPK signalling pathway.

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“…Previous reports have shown that oxidative stress may be cell toxic for cardiac myocytes . DCFH‐DA fluorescence probe was performed to measure ROS of different groups in vitro.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high‐fat diet‐induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway

Zuo

Zhao

et al. 2020

J Cellular Molecular Medi

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“…Inflammation and oxidative stress have been reported to markedly affect the development and progression of diabetes, as well as its complications (8,9). Additionally, previous studies have indicated that uncontrolled inflammation and oxidative stress may contribute to cardiac dysfunction in diabetic cardiac tissues (10,11). Extensive research has also revealed that mitochondrial injury may serve as a central mediator in the pathology of DCM (12,13).…”

Section: Introductionmentioning

confidence: 99%

SIRT6‑specific inhibitor OSS‑128167 exacerbates diabetic cardiomyopathy by aggravating inflammation and oxidative stress

Huang

Zhang

et al. 2021

Mol Med Rep

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Diabetic cardiomyopathy (DCM) is a serious complication of diabetes, which importantly contributes to the increased mortality of patients with diabetes. The development of DCM is accompanied by numerous pathological mechanisms, including oxidative stress and chronic inflammation. Accordingly, the present study aimed to determine the effects of the sirtuin 6 (SIRT6) inhibitor OSS-128167 on DCM using a mouse model of streptozotocin (STZ)-induced diabetes and high glucose (HG)-treated cardiomyocytes. C57BL/6 mice were intraperitoneally injected with STZ for 5 days to simulate the diabetic cardiomyopathy model. Mice with STZ-induced diabetes (STZ-DM1) were orally administered OSS-128167 (20 or 50 mg/kg) through gavage every other day. The expression of SIRT6 in myocardial tissue was detected using western blotting. Tissue staining (hematoxylin and eosin and Masson's trichrome) was used to characterize myocardial structure, TUNEL fluorescent staining was used to detect myocardial apoptosis, and immunohistochemical staining was used to detect the expression of inflammatory factors in myocardial tissue. Dihydroethidium staining and a malondialdehyde (MDA) detection kit were used to detect the oxidative stress levels in myocardial tissues. In vitro, H9c2 cells were pre-incubated with OSS-128167 for 1 h and then stimulated with HG (33 mM) for various durations. Expression levels of fibrosis markers, collagen-1 and transforming growth factor (TGF)-β, apoptosis-related proteins, Bax, Bcl-2 and cleaved-poly ADP-ribose polymerase, tumor necrosis factor-α and the oxidative stress metabolite, 3-nitrotyrosine were analyzed using western blotting and reverse transcription-quantitative PCR. Commercially available kits were used to detect the activity of caspase-3 and the content of MDA in the H9c2 cell line. The corresponding results demonstrated that OSS-128167 aggravated diabetes-induced cardiomyocyte apoptosis and fibrosis in mice. Mechanistically, OSS-128167 was revealed to increase the levels of inflammatory factors and reactive oxygen species (ROS) in vitro and in vivo. In conclusion, OSS-128167 facilitated the inflammatory response and promoted the production of ROS while aggravating DCM development. These findings indicated that SIRT6 may target two closely combined and interacting pathological processes, the inflammatory response and oxidative stress, and may serve as a potentially advantageous therapeutic target.

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“…Interestingly, loss of GCN2 function resulted in increased expression of the anti-apoptotic factor Bcl-2, along with a reduction in both oxidative stress and cardiomyocyte cell death via apoptosis [53]. Another study conducted on diabetic GCN2 −/− mice demonstrated reduction in lipotoxicity and oxidative stress [54]. Together, these studies provide an explanation for the cardioprotective role of GCN2 deletion.…”

Section: Translation Initiation Factor Eif2mentioning

confidence: 90%

“…On the contrary, in vivo treatment of male C57Bl/6J mice and human cardiac fibroblasts with halofuginone, a bioactive compound that induces the GCN2-mediated stress response pathway, also resulted in improved survival, ventricular function, and reduced ischemic injury in mice [55]. These contradictory findings most likely stem from the fact that different experimental systems were used [53][54][55]. It is also possible that, in addition to activating the GCN2-stress response pathway, halofuginone may have off-target effects; thus, these data cannot be directly compared to the effects of a permanent deletion of GCN2 on the cardiac system.…”

Section: Translation Initiation Factor Eif2mentioning

confidence: 99%

Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

Ghosh

Shcherbik

2020

IJMS

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Cardiovascular diseases (CVDs) are a group of disorders that affect the heart and blood vessels. Due to their multifactorial nature and wide variation, CVDs are the leading cause of death worldwide. Understanding the molecular alterations leading to the development of heart and vessel pathologies is crucial for successfully treating and preventing CVDs. One of the causative factors of CVD etiology and progression is acute oxidative stress, a toxic condition characterized by elevated intracellular levels of reactive oxygen species (ROS). Left unabated, ROS can damage virtually any cellular component and affect essential biological processes, including protein synthesis. Defective or insufficient protein translation results in production of faulty protein products and disturbances of protein homeostasis, thus promoting pathologies. The relationships between translational dysregulation, ROS, and cardiovascular disorders will be examined in this review.

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GCN2 deficiency ameliorates cardiac dysfunction in diabetic mice by reducing lipotoxicity and oxidative stress

Cited by 38 publications

References 57 publications

CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high‐fat diet‐induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway

CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high‐fat diet‐induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway

SIRT6‑specific inhibitor OSS‑128167 exacerbates diabetic cardiomyopathy by aggravating inflammation and oxidative stress

Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

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