School of Medicine, Nantong University, Nantong, Jiangsu 226001, China.
School of Pharmacy, Nantong University, Nantong, Jiangsu 226001, China.
Oxid Med Cell Longev. 2022 Jul 28;2022:7941374. doi: 10.1155/2022/7941374. eCollection 2022.
The activity of Ca/calmodulin-dependent protein kinase II (CaMKII ) is central to the mechanisms of cardiovascular diseases. Receptor-interacting protein kinase 3- (RIPK3-) mediated necroptosis has been reported to contribute to cardiac dysfunction. However, the potential protective role of inhibition of RIPK3, a regulator of CaMKII, on cardiac hypertrophy remains unclear. The present study is aimed at investigating how the RIPK3 inhibitor GSK'872 regulates CaMKII activity and exploring its effect on hypertrophic cardiomyopathy (HCM). Wild-type (WT) and RIPK3 gene knockout (RIPK3) mice were implanted subcutaneously with Alzet miniosmotic pumps (200 L) and perfused with angiotensin II (AMP-AngII) to induce cardiac hypertrophy. After WT mice were induced by AngII for 72 hours, they were injected with GSK'872 with an intraperitoneal (IP) dose of 6 mg/kg once a day for two weeks. After this, they were physiologically examined for Echocardiography, myocardial injury, CaMKII activity, necroptosis, RIPK3 expression, mixed lineage kinase domain-like protein (MLKL) phosphorylation, and mitochondrial ultrastructure. The results indicated that deletion of the RIPK3 gene or administration of GSK'872 could reduce CaMKII activity, alleviate oxidative stress, reduce necroptosis, and reverse myocardial injury and cardiac dysfunction caused by AngII-induced cardiac hypertrophy in mice. The present study demonstrated that CaMKII activation and necroptosis augment cardiac hypertrophy in a RIPK3-dependent manner, which may provide therapeutic strategies for HCM. RIPK3 inhibitor GSK'872 has a protective effect on cardiac hypertrophy and could be an efficacious targeted medicine for HCM in clinical treatment.
钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）的活性是心血管疾病机制的核心。已报道受体相互作用蛋白激酶 3（RIPK3）介导的坏死性凋亡有助于心脏功能障碍。然而，作为 CaMKII 调节剂的 RIPK3 抑制的潜在保护作用对心肌肥厚尚不清楚。本研究旨在研究 RIPK3 抑制剂 GSK'872 如何调节 CaMKII 活性，并探讨其对肥厚型心肌病（HCM）的影响。野生型（WT）和 RIPK3 基因敲除（RIPK3）小鼠皮下植入 Alzet 微型渗透泵（200μL），并灌注血管紧张素 II（AMP-AngII）以诱导心肌肥厚。在 WT 小鼠用 AngII 诱导 72 小时后，每天腹腔内（IP）注射 6mg/kg 的 GSK'872 一次，共两周。之后，对它们进行超声心动图、心肌损伤、CaMKII 活性、坏死性凋亡、RIPK3 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的生理检查。结果表明，RIPK3 基因缺失或 GSK'872 给药可降低 CaMKII 活性，减轻氧化应激，减少坏死性凋亡，并逆转 AngII 诱导的心肌肥厚引起的心肌损伤和心脏功能障碍。本研究表明，CaMKII 的激活和坏死性凋亡以 RIPK3 依赖的方式增强心肌肥厚，这可能为 HCM 提供治疗策略。RIPK3 抑制剂 GSK'872 对心肌肥厚具有保护作用，可能成为 HCM 临床治疗的有效靶向药物。
