RIPK3-Mediated Necroptosis in Diabetic Cardiomyopathy Requires CaMKII Activation.
RIPK3-Mediated Necroptosis in Diabetic Cardiomyopathy Requires CaMKII Activation.
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糖尿病心肌病中 RIPK3 介导的坏死性凋亡需要 CaMKII 激活
DOI：
10.1155/2021/6617816
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发表时间：
2021
影响因子：
--
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Chen Y;Li X;Hua Y;Ding Y;Meng G;Zhang W
Ca2+/钙调蛋白依赖性蛋白激酶（CaMKII）的激活已被证明在心血管疾病中发挥着至关重要的作用。受体相互作用蛋白激酶 3- (RIPK3-) 介导的坏死性凋亡在心脏功能障碍中发挥着重要作用。本研究旨在探讨CaMKII激活和坏死性凋亡对糖尿病心肌病（DCM）的影响及其机制。野生型（WT）和RIPK3基因敲除（RIPK3−/−）小鼠腹腔注射链脲佐菌素（STZ）60mg/kg/d，连续5天。喂养12周后，将100μL携带蛋白磷酸酶1（I1PP1）基因抑制剂1的重组腺病毒溶液注射到小鼠尾静脉中。测量超声心动图、心肌损伤、CaMKII 活性、坏死性凋亡、RIPK1 表达、混合谱系激酶结构域样蛋白 (MLKL) 磷酸化和线粒体超微结构。结果表明，链脲佐菌素 (STZ-) 刺激的小鼠以及 (Lepr) KO/KO (db/db) 小鼠的心脏功能障碍、CaMKII 激活和坏死性凋亡均加重。 RIPK3 缺乏可减轻扩张型心肌病 (DCM) 中的心脏功能障碍、CaMKII 激活和坏死性凋亡。此外，在患有 DCM 的 WT 小鼠中，I1PP1 过表达可逆转心脏功能障碍、心肌损伤和坏死性凋亡，并且 CaMKII 活性增强，但在患有 DCM 的 RIPK3−/− 小鼠中则不然。本研究表明，DCM 中 CaMKII 激活和坏死性凋亡通过 RIPK3 依赖性方式增强，这可能为 DCM 提供治疗策略。
Activation of Ca2+/calmodulin-dependent protein kinase (CaMKII) has been proved to play a vital role in cardiovascular diseases. Receptor-interaction protein kinase 3- (RIPK3-) mediated necroptosis has crucially participated in cardiac dysfunction. The study is aimed at investigating the effect as well as the mechanism of CaMKII activation and necroptosis on diabetic cardiomyopathy (DCM). Wild-type (WT) and the RIPK3 gene knockout (RIPK3−/−) mice were intraperitoneally injected with 60 mg/kg/d streptozotocin (STZ) for 5 consecutive days. After 12 w of feeding, 100 μL recombinant adenovirus solution carrying inhibitor 1 of protein phosphatase 1 (I1PP1) gene was injected into the caudal vein of mice. Echocardiography, myocardial injury, CaMKII activity, necroptosis, RIPK1 expression, mixed lineage kinase domain-like protein (MLKL) phosphorylation, and mitochondrial ultrastructure were measured. The results showed that cardiac dysfunction, CaMKII activation, and necroptosis were aggravated in streptozotocin- (STZ-) stimulated mice, as well as in (Lepr) KO/KO (db/db) mice. RIPK3 deficiency alleviated cardiac dysfunction, CaMKII activation, and necroptosis in DCM. Furthermore, I1PP1 overexpression reversed cardiac dysfunction, myocardial injury and necroptosis augment, and CaMKII activity enhancement in WT mice with DCM but not in RIPK3−/− mice with DCM. The present study demonstrated that CaMKII activation and necroptosis augment in DCM via a RIPK3-dependent manner, which may provide therapeutic strategies for DCM.
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影响因子：
5
作者：
Neef S;Steffens A;Pellicena P;Mustroph J;Lebek S;Ort KR;Schulman H;Maier LS
通讯作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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DOI：
10.1186/s13046-019-1201-4
发表时间：
2019-05-28
影响因子：
11.3
作者：
Hu, Jinjiao;Zhang, Yanhao;Gao, Ning
通讯作者：
Gao, Ning