Cao Zhi, Li Weifeng, Shao Zhuang, Liu Xinqiang, Zeng Yi, Lin Peijun, Lin Chuangqiang, Zhao Yuechu, Li Ting, Zhao Zichao, Li Xin, Zhang Yuelin, Hu Bei
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
Medical College, Shantou University, Shantou, Guangdong, China.
Heliyon. 2024 Jan 23;10(3):e24568. doi: 10.1016/j.heliyon.2024.e24568. eCollection 2024 Feb 15.
Sepsis-induced myocardial dysfunction (SMD) is the major cause of death in sepsis. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)-mediated pyroptosis contributes to the occurrence and development of SMD. Although Apelin confers direct protection against SMD, the potential mechanisms remain unclear. This study aimed to determine whether Apelin protects against SMD via regulation of NLRP3-mediated pyroptosis of cardiomyocytes. Experimental SMD was induced in wild-type (WT) control mice and Apelin knockout (Apelin) mice by cecal ligation and puncture (CLP). Neonatal mouse cardiomyocytes (NMCs) were treated with lipopolysaccharide (LPS) to simulate the physiological environment of SMD . The expression of Apelin was greatly decreased in the plasma from septic patients and septic mouse heart. Knockout of Apelin aggravated SMD, evidenced by decreased cardiac function, and increased cardiac fibrosis and NLRP3 inflammasome and pyroptosis levels in CLP-treated Apelin mice compared with WT mice. Overexpression of Apelin activated the AMPK pathway and thereby inhibited NLRP3 inflammasome-mediated pyroptosis of NMCs induced by LPS These protective effects were partially abrogated by AMPK inhibitor. In conclusion, Apelin attenuated SMD by inhibiting NLRP3-mediated pyroptosis via activation of the AMPK pathway. Apelin may serve as a promising therapeutic target for SMD.
脓毒症诱导的心肌功能障碍（SMD）是脓毒症患者死亡的主要原因。含核苷酸结合寡聚化结构域样受体家族吡啉结构域3（NLRP3）介导的细胞焦亡参与了SMD的发生和发展。尽管Apelin对SMD具有直接保护作用，但其潜在机制尚不清楚。本研究旨在确定Apelin是否通过调节NLRP3介导的心肌细胞焦亡来保护心肌免受SMD损伤。通过盲肠结扎穿孔术（CLP）在野生型（WT）对照小鼠和Apelin基因敲除（Apelin-/-）小鼠中诱导实验性SMD。用脂多糖（LPS）处理新生小鼠心肌细胞（NMCs）以模拟SMD的生理环境。脓毒症患者血浆和脓毒症小鼠心脏中Apelin的表达显著降低。与WT小鼠相比，Apelin基因敲除加重了CLP处理的Apelin-/-小鼠的SMD，表现为心功能下降、心脏纤维化增加以及NLRP3炎性小体和细胞焦亡水平升高。Apelin过表达激活了AMPK通路，从而抑制了LPS诱导的NMCs的NLRP3炎性小体介导的细胞焦亡。这些保护作用被AMPK抑制剂部分消除。总之，Apelin通过激活AMPK通路抑制NLRP3介导的细胞焦亡，从而减轻SMD。Apelin可能是治疗SMD有前景的治疗靶点。
