Changes of Necroptosis in Irbesartan Medicated Cardioprotection in Diabetic Rats

Xu, Qingmei; Tan, Xin; Wei, Xian; Geng, Jiayi; Li, Haoyu; Tang, Bi; Zhang, Heng; Wang, Hongju; Gao, Qin; Kang, Pan

doi:10.2147/dmso.s300388

Cited by 8 publications

(5 citation statements)

References 36 publications

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“…Furthermore, hyperglycemia induces excessive generation of reactive oxygen species (ROS), which may also initiate inflammatory response and trigger progressive mitochondrial damage and cardiomyocyte apoptosis in diabetic heart, finally leading to cardiac dysfunction, remodeling and heart failure [13]. Recent studies have reported that necroptosis is also involved in DCM [14][15][16]. Necroptosis is a highly inflammatory form of cell death, which is triggered by receptor interacting kinase 1 (RIPK1), then binds to receptor interacting kinase 3 (RIPK3) and subsequently recruits and phosphorylates mixed lineage kinase domain-like protein (MLKL).…”

Section: Introductionmentioning

confidence: 99%

Dihydromyricetin Attenuates Diabetic Cardiomyopathy by Inhibiting Oxidative Stress, Inflammation and Necroptosis via Sirtuin 3 Activation

et al. 2023

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Dihydromyricetin (DHY), the main flavonoid component in Ampelopsis grossedentata, has important benefits for health. The present study aimed to investigate the exact effects and possible mechanisms of DHY on diabetic cardiomyopathy (DCM). Male C57BL/6 mice and sirtuin 3 (SIRT3) knockout (SIRT3-KO) mice were injected with streptozotocin (STZ) to induce a diabetic model. Two weeks later, DHY (250 mg/kg) or carboxymethylcellulose (CMC) were administrated once daily by gavage for twelve weeks. We found that DHY alleviated fasting blood glucose (FBG) and triglyceride (TG) as well as glycosylated hemoglobin (HbA1c) levels; increased fasting insulin (FINS); improved cardiac dysfunction; ameliorated myocardial hypertrophy, fibrosis and injury; suppressed oxidative stress, inflammasome and necroptosis; but improved SIRT3 expression in STZ-induced mice. Neonatal rat cardiomyocytes were pre-treated with DHY (80 μM) with or without high glucose (HG) stimulation. The results showed that DHY attenuated cell damage but improved SIRT3 expression and inhibited oxidative stress, inflammasome and necroptosis in cardiomyocytes with high glucose stimulation. Moreover, the above protective effects of DHY on DCM were unavailable in SIRT3-KO mice, implying a promising medical potential of DHY for DCM treatment. In sum, DHY improved cardiac dysfunction; ameliorated myocardial hypertrophy, fibrosis and injury; and suppressed oxidative stress, inflammation and necroptosis via SIRT3 activation in STZ-induced diabetic mice, suggesting DHY may serve as a candidate for an agent to attenuate diabetic cardiomyopathy.

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Section: Introductionmentioning

confidence: 99%

Dihydromyricetin Attenuates Diabetic Cardiomyopathy by Inhibiting Oxidative Stress, Inflammation and Necroptosis via Sirtuin 3 Activation

et al. 2023

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“…These in vitro studies have engaged the necroptosis signaling in high glucose-induced cardiomyocyte death. In animal models of diabetes including STZ injection-induced type-1 diabetic mice [ 27 ], high fat diet-induced pre-diabetic rats [ 25 ], high fat diet plus STZ-induced type-2 diabetic rats [ 43 ] and db/db type-2 diabetic mice [ 27 ], the protein levels of total and/or phosphorylated RIPK1/RIPK3/MLKL were elevated in the heart, suggesting a potential role of necroptosis in cardiac complications of diabetes. Indeed, this was supported by a most recent study which showed that deletion of RIPK3 alleviated myocardial injury and dysfunction in STZ-injected mice [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, our data demonstrate that in addition to apoptosis and pyroptosis, cardiomyocyte necroptosis also makes important contribution to the pathogenesis of type-1 diabetic cardiomyopathy and represents a target for cardiac protection in diabetes. Although the current study was focused on type-1 diabetes, we speculate that cardiomyocyte necroptosis may also play a role in cardiac pathology of type-2 diabetes as the necroptosis signaling RIPK3 and MLKL were activated in the heart of db/db type-2 diabetic mice [ 27 ] and high fat diet plus STZ-induced type-2 diabetic rats [ 43 ]. Nevertheless, future studies are warranted to clarify the role of necroptosis and its RIPK3/MLKL signaling in cardiac pathology using type-2 diabetic models.…”

Section: Discussionmentioning

confidence: 99%

MLKL-mediated necroptosis is a target for cardiac protection in mouse models of type-1 diabetes

Cao

Ding

et al. 2022

Cardiovasc Diabetol

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Background Cardiomyocyte death contributes to cardiac pathology of diabetes. Studies have shown that the RIPK3/MLKL necroptosis signaling is activated in diabetic hearts. Deletion of RIPK3 was reported to attenuate myocardial injury and heart dysfunction in streptozocin (STZ)-induced diabetic mice, suggesting a potential role of necroptosis in diabetic cardiomyopathy. This study characterized cardiomyocyte necroptosis in diabetic hearts and investigated whether MLKL-mediated necroptosis is a target for cardiac protection in diabetes. Methods Type 1 diabetes was induced in RIPK3 knockout, MLKL knockout and wild-type mice. Akita Type-1 diabetic mice were injected with shRNA for MLKL. Myocardial function was assessed by echocardiography. Immuno-histological analyses determined cardiomyocyte death and fibrosis in the heart. Cultured adult mouse cardiomyocytes were incubated with high glucose in the presence of various drugs. Cell death and phosphorylation of RIPK3 and MLKL were analysed. Results We showed that the levels of phosphorylated RIPK3 and MLKL were higher in high glucose-stimulated cardiomyocytes and hearts of STZ-induced type-1 diabetic mice, akita mice and type-1 diabetic monkeys when compared to non-diabetic controls. Inhibition of RIPK3 by its pharmacological inhibitor or gene deletion, or MLKL deletion prevented high glucose-induced MLKL phosphorylation and attenuated necroptosis in cardiomyocytes. In STZ-induced type-1 diabetic mice, cardiomyocyte necroptosis was present along with elevated cardiac troponin I in serum and MLKL oligomerization, and co-localized with phosphorylated MLKL. Deletion of RIPK3 or MLKL prevented MLKL phosphorylation and cardiac necroptosis, attenuated serum cardiac troponin I levels, reduced myocardial collagen deposition and improved myocardial function in STZ-injected mice. Additionally, shRNA-mediated down-regulation of MLKL reduced cardiomyocyte necroptosis in akita mice. Interestingly, incubation with anti-diabetic drugs (empagliflozin and metformin) prevented phosphorylation of RIPK3 and MLKL, and reduced cell death in high glucose-induced cardiomyocytes. Conclusions We have provided evidence that cardiomyocyte necroptosis is present in diabetic hearts and that MLKL-mediated cardiomyocyte necroptosis contributes to diabetic cardiomyopathy. These findings highlight MLKL-mediated necroptosis as a target for cardiac protection in diabetes.

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“…Necroptosis also has implications in diabetic complications. Elevated total and/or phosphorylated RIPK1/RIPK3/MLKL levels have been observed in the hearts of either type 1 or type 2 diabetes animal models, 103 underscoring the role of necroptosis in the pathogenesis of diabetes complications. Notably, lipotoxicity contributes to increased necroptosis levels under diabetic conditions.…”

Section: Lipotoxicity Mediates the Detrimental Effects Of Diabetes On...mentioning

confidence: 97%

Lipotoxicity: The missing link between diabetes and periodontitis?

Sun,

Yin,

Yang

et al. 2024

J of Periodontal Research

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Lipotoxicity refers to the accumulation of lipids in tissues other than adipose tissue (body fat). It is one of the major pathophysiological mechanisms responsible for the progression of diabetes complications such as non‐alcoholic fatty liver disease and diabetic nephropathy. Accumulating evidence indicates that lipotoxicity also contributes significantly to the toxic effects of diabetes on periodontitis. Therefore, we reviewed the current in vivo, in vitro, and clinical evidence of the detrimental effects of lipotoxicity on periodontitis, focusing on its molecular mechanisms, especially oxidative and endoplasmic reticulum stress, inflammation, ceramides, adipokines, and programmed cell death pathways. By elucidating potential therapeutic strategies targeting lipotoxicity and describing their associated mechanisms and clinical outcomes, including metformin, statins, liraglutide, adiponectin, and omega‐3 PUFA, this review seeks to provide a more comprehensive and effective treatment framework against diabetes‐associated periodontitis. Furthermore, the challenges and future research directions are proposed, aiming to contribute to a more profound understanding of the impact of lipotoxicity on periodontitis.

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Changes of Necroptosis in Irbesartan Medicated Cardioprotection in Diabetic Rats

Cited by 8 publications

References 36 publications

Dihydromyricetin Attenuates Diabetic Cardiomyopathy by Inhibiting Oxidative Stress, Inflammation and Necroptosis via Sirtuin 3 Activation

Dihydromyricetin Attenuates Diabetic Cardiomyopathy by Inhibiting Oxidative Stress, Inflammation and Necroptosis via Sirtuin 3 Activation

MLKL-mediated necroptosis is a target for cardiac protection in mouse models of type-1 diabetes

Lipotoxicity: The missing link between diabetes and periodontitis?

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