MLKL-mediated necroptosis is a target for cardiac protection in mouse models of type-1 diabetes.
MLKL-mediated necroptosis is a target for cardiac protection in mouse models of type-1 diabetes.
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DOI：
10.1186/s12933-022-01602-9
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发表时间：
2022-08-27
影响因子：
9.3
通讯作者：
Peng, Tianqing
中科院分区：
文献类型：
--
作者：
Cao, Ting;Ni, Rui;Ding, Weimin;Ji, Xiaoyun;Li, Lan;Liao, Guangneng;Lu, Yanrong;Fan, Guo-Chang;Zhang, Zhuxu;Peng, Tianqing
心肌细胞死亡有助于糖尿病的心脏病理。研究表明，RIPK 3/MLKL坏死性凋亡信号在糖尿病心脏中被激活。据报道，RIPK 3的缺失可减轻链脲佐菌素（STZ）诱导的糖尿病小鼠的心肌损伤和心脏功能障碍，表明坏死性凋亡在糖尿病心肌病中的潜在作用。本研究描述了糖尿病心脏中心肌细胞坏死性凋亡的特征，并研究了MLKL介导的坏死性凋亡是否是糖尿病心脏保护的靶点。在RIPK 3敲除、MLKL敲除和野生型小鼠中诱导1型糖尿病。给秋田1型糖尿病小鼠注射MLKL的shRNA。超声心动图评价心肌功能。免疫组织学分析确定心肌细胞死亡和心脏纤维化。将培养的成年小鼠心肌细胞在存在各种药物的情况下与高糖一起孵育。分析细胞死亡和RIPK 3和MLKL的磷酸化。我们发现，与非糖尿病对照组相比，磷酸化RIPK 3和MLKL的水平在高糖刺激的心肌细胞和STZ诱导的1型糖尿病小鼠，秋田小鼠和1型糖尿病猴的心脏中更高。通过其药理学抑制剂或基因缺失或MLKL缺失抑制RIPK 3可防止高糖诱导的MLKL磷酸化并减弱心肌细胞中的坏死性凋亡。在STZ诱导的1型糖尿病小鼠中，心肌细胞坏死性凋亡与血清中心肌肌钙蛋白I升高和MLKL寡聚化一起存在沿着，并与磷酸化MLKL共定位。RIPK 3或MLKL的缺失防止MLKL磷酸化和心脏坏死性凋亡，降低血清心肌肌钙蛋白I水平，减少心肌胶原沉积，改善STZ注射小鼠的心肌功能。此外，shRNA介导的MLKL下调减少了秋田小鼠的心肌细胞坏死性凋亡。有趣的是，与抗糖尿病药物（恩格列净和二甲双胍）一起孵育可阻止RIPK 3和MLKL的磷酸化，并减少高糖诱导的心肌细胞中的细胞死亡。我们提供的证据表明，心肌细胞坏死存在于糖尿病心脏和MLKL介导的心肌细胞坏死有助于糖尿病心肌病。这些发现突出了MLKL介导的坏死性凋亡作为糖尿病心脏保护的靶点。在线版本包含补充材料，可通过10.1186/s12933-022-01602-9获得。
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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s12933-022-01602-9.
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