ArticleCardiovascular diabetology2022
MLKL-mediated necroptosis is a target for cardiac protection in mouse models of type-1 diabetes.
Article in Cardiovascular diabetology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 44 citations in OpenAlex.
- Targeting MLKL-Driven Necroptosis: A Therapeutic Target in Inflammation and Host Defense.Biomolecules · 2026Review
- Regulated Cell Death and Inflammatory Signaling in Diabetic Cardiomyopathy: Mechanisms and Therapeutic Strategies.Journal of cardiovascular translational research · 2025Review
- Life-threatening risk factors contribute to the development of diseases with the highest mortality through the induction of regulated necrotic cell death.Cell death & disease · 2025Review
- Necrosis-like cell death modes in heart failure: the influence of aetiology and the effects of RIP3 inhibition.Basic research in cardiology · 2025Article
- DNA damage-inducible transcript 3 positively regulates RIPK1-mediated necroptosis.Cell death and differentiation · 2025Article
- Inflammatory adhesion mediates myocardial segmental necroptosis induced by mixed lineage kinase domain-like protein in acute myocardial infarction.Cell communication and signaling : CCS · 2025Article
- Baihu Jia Renshen Decoction Improves Type 1 Diabetic Rats by Modulating Metabolic Profile.International journal of endocrinology · 2025Article
- Roles of Empagliflozin in Diabetic Cardiomyopathy: A Review.Current vascular pharmacology · 2025Review
- Types of cell death in diabetic cardiomyopathy: insights from animal models.Acta biochimica et biophysica Sinica · 2024Review
- The study of the mechanism of non-coding RNA regulation of programmed cell death in diabetic cardiomyopathy.Molecular and cellular biochemistry · 2024Review
- The role of regulated necrosis in diabetes and its complications.Journal of molecular medicine (Berlin, Germany) · 2024Review
- The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7.Cardiovascular diabetology · 2024Review
- Landscape of molecular crosstalk between SARS-CoV-2 infection and cardiovascular diseases: emphasis on mitochondrial dysfunction and immune-inflammation.Journal of translational medicine · 2023Article
- Analysis of Signaling Pathways of Necroptotic and Pyroptotic Cell Death in the Hearts of Rats With Type 2 Diabetes Mellitus.Physiological research · 2023Article
- Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study.Journal of translational medicine · 2023Article
- Progress in study on the final executor of necroptosis MLKL and its inhibitors.Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2023Article
- Early longitudinal changes in left ventricular function and morphology in diabetic pigs: evaluation by 3.0T magnetic resonance imaging.Cardiovascular diabetology · 2023Article
- Ferroptosis, necroptosis and cuproptosis: Novel forms of regulated cell death in diabetic cardiomyopathy.Frontiers in cardiovascular medicine · 2023Review
- Approaches to Evaluating Necroptosis in Virus-Infected Cells.Sub-cellular biochemistry · 2023Article
- Ferroptosis: Underlying mechanism and the crosstalk with other modes of neuronal death after intracerebral hemorrhage.Frontiers in cellular neuroscience · 2023Review
Corrections and comments
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Authors and funding
10 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCardiomyocyte 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.
methodsType 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.
resultsWe 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.
conclusionsWe 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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