A novel complement C3 inhibitor CP40-KK protects against experimental pulmonary arterial hypertension via an inflammasome NLRP3 associated pathway

被引：6

作者：

Dai, Lei ^{[1
,2
]}

Chen, Yu ^{[1
,2
]}

Wu, Jinhua ^{[3
]}

He, Zhen ^{[1
,2
]}

Zhang, Yueqi ^{[1
,2
]}

Zhang, Wenjun ^{[1
,2
]}

Xie, Yang ^{[1
,2
]}

Zeng, Hesong ^{[1
,2
]}

Zhong, Xiaodan ^{[1
,2
]}

机构：

[1] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Div Cardiol,Dept Internal Med, Wuhan 430030, Peoples R China

[2] Hubei Prov Engn Res Ctr Vasc Intervent Therapy, Wuhan 430030, Hubei, Peoples R China

[3] Peoples Hosp Guangxi Zhuang Autonomous Reg, Dept Gastroenterol, Nanning 530000, Guangxi, Peoples R China

来源：

JOURNAL OF TRANSLATIONAL MEDICINE | 2024年 / 22卷 / 01期

基金：

中国国家自然科学基金;

关键词：

Pulmonary arterial hypertension; Complement C3; CP40-KK; NLRP3; Proinflammatory cytokine; IN-VITRO; COMPSTATIN; ACTIVATION; HYPOXIA; DYSREGULATION; LEUKOSTASIS; DYSFUNCTION; MONOCYTES; BINDING; ABSENCE;

D O I：

10.1186/s12967-023-04741-z

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Background Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disease characterized by complement dependent and proinflammatory activation of macrophages. However, effective treatment for complement activation in PAH is lacking. We aimed to explore the effect and mechanism of CP40-KK (a newly identified analog of selective complement C3 inhibitor CP40) in the PAH model. Methods We used western blotting, immunohistochemistry, and immunofluorescence staining of lung tissues from the monocrotaline (MCT)-induced rat PAH model to study macrophage infiltration, NLPR3 inflammasome activation, and proinflammatory cytokines (IL-1 beta and IL-18) release. Surface plasmon resonance (SPR), ELISA, and CH50 assays were used to test the affinity between CP40-KK and rat/human complement C3. CP40-KK group rats only received CP40-KK (2 mg/kg) by subcutaneous injection at day 15 to day 28 continuously. Results C3a was significantly upregulated in the plasma of MCT-treated rats. SPR, ELISA, and CH50 assays revealed that CP40-KK displayed similar affinity binding to human and rat complement C3. Pharmacological inhibition of complement C3 cleavage (CP40-KK) could ameliorate MCT-induced NLRP3 inflammasome activity, pulmonary vascular remodeling, and right ventricular hypertrophy. Mechanistically, increased proliferation of pulmonary arterial smooth muscle cells is closely associated with macrophage infiltration, NLPR3 inflammasome activation, and proinflammatory cytokines (IL-1 beta and IL-18) release. Besides, C3a enhanced IL-1 beta activity in macrophages and promoted pulmonary arterial smooth muscle cell proliferation in vitro. Conclusion Our findings suggest that CP40-KK treatment was protective in the MCT-induced rat PAH model, which might serve as a therapeutic option for PAH.

引用

页数：13