Department of Cardiology, Fifth People's Hospital of Chengdu, Chengdu, PR China.
Department of Cardiology, Chengdu University of Traditional Chinese Medicine Affiliated Fifth People's Hospital, Chengdu, China.
Bioengineered. 2022 Apr;13(4):8593-8604. doi: 10.1080/21655979.2022.2053813.
MCC950, a specific NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inhibitor, has been reported to play a role in various cardiovascular diseases. However, its role in heart failure (HF)-induced ventricular arrhythmias (VAs) remains unclear. Hence, the present study aimed to clarify the role and underlying mechanisms of MCC950 in HF-induced VAs. Male C57BL/6 mice were induced with HF via transverse aortic constriction (TAC). Histological analysis, echocardiography, electrophysiological investigation, and western blot analysis were conducted to evaluate VA vulnerability induced by TAC and the potential mechanisms underlying the effects. MCC950 markedly improved cardiac function and decreased pulmonary edema induced by HF. Moreover, MCC950 also decreased VA vulnerability, as shown by the shortened QTc duration and action potential duration 90 (APD), reduced APD alternans threshold, and decreased VA induction rate. Furthermore, MCC950 treatment significantly reversed TAC-induced cardiac hypertrophy and fibrosis. In addition, MCC950 administration increased the protein levels of ion channels (Kv4.2, KChIP2, and Cav1.2). Mechanistically, the above changes induced by MCC950 were due to the inhibition of the NLRP3 inflammasome. As a specific NLRP3 inhibitor, MCC950 significantly decreased HF-induced VA vulnerability by reversing cardiac structural remodeling and electrical remodeling, and the mechanism through which MCC950 exhibited this effect was inhibition of NLRP3 inflammasome activation.
MCC950 是一种特异性 NACHT、LRR 和 PYD 结构域包含蛋白 3（NLRP3）抑制剂，已被报道在多种心血管疾病中发挥作用。然而，其在心力衰竭（HF）诱导的室性心律失常（VA）中的作用尚不清楚。因此，本研究旨在阐明 MCC950 在 HF 诱导的 VA 中的作用及其潜在机制。雄性 C57BL/6 小鼠通过横主动脉缩窄（TAC）诱导 HF。进行组织学分析、超声心动图、电生理研究和 Western blot 分析，以评估 TAC 诱导的 VA 易损性及其潜在作用机制。MCC950 显著改善了 HF 引起的心脏功能障碍和肺水肿。此外，MCC950 还降低了 VA 易损性，表现为 QTc 间期缩短和动作电位时程 90（APD）缩短，APD 交替阈值降低，VA 诱导率降低。此外，MCC950 治疗显著逆转了 TAC 诱导的心脏肥大和纤维化。此外，MCC950 给药增加了离子通道（Kv4.2、KChIP2 和 Cav1.2）的蛋白水平。机制上，MCC950 引起的上述变化归因于 NLRP3 炎性小体的抑制。作为一种特异性 NLRP3 抑制剂，MCC950 通过逆转心脏结构重塑和电重塑显著降低 HF 诱导的 VA 易损性，MCC950 发挥此作用的机制是抑制 NLRP3 炎性小体的激活。
