Lp-PLA2 inhibition prevents Ang Ⅱ-induced cardiac inflammation and fibrosis by blocking macrophage NLRP3 inflammasome activation

• 作者: Si-lin Lv Zi-fan Zeng Wen-qiang Gan Wei-qi Wang Tie-gang Li Yu-fang Hou Zheng Yan Ri-xin Zhang Min Yang
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（12）
• 所属期刊栏目: Cardiovascular Pharmacology
• 页码范围: 2016-2032
• 页数: 17页
• 语种: 英文

摘要

Macrophage-mediated inflammation plays an important role in hypertensive cardiac remodeling,whereas effective pharmacological treatments targeting cardiac inflammation remain unclear.Lipoprotein-associated phospholipase A2 (Lp-PLA2)contributes to vascular inflammation-related diseases by mediating macrophage migration and activation.Darapladib,the most advanced Lp-PLA2 inhibitor,has been evaluated in phase Ⅲ trials in atherosclerosis patients.However,the role of darapladib in inhibiting hypertensive cardiac fibrosis remains unknown.Using a murine angiotensin Ⅱ (Ang Ⅱ) infusion-induced hypertension model,we found that Pla2g7 (the gene of Lp-PLA2) was the only upregulated PLA2 gene detected in hypertensive cardiac tissue,and it was primarily localized in heart-infiltrating macrophages.As expected,darapladib significantly prevented Ang Ⅱ-induced cardiac fibrosis,ventricular hypertrophy,and cardiac dysfunction,with potent abatement of macrophage infiltration and inflammatory response.RNA sequencing revealed that darapladib strongly downregulated the expression of genes and signaling pathways related to inflammation,extracellular matrix,and proliferation.Moreover,darapladib substantially reduced the Ang Ⅱinfusion-induced expression of nucleotide-binding oligomerization domain-like receptor with pyrin domain 3 (NLRP3) and interleukin (IL)-1β and markedly attenuated caspase-1 activation in cardiac tissues.Furthermore,darapladib ameliorated Ang Ⅱ-stimulated macrophage migration and IL-1β secretion in macrophages by blocking NLRP3 inflammasome activation.Darapladib also effectively blocked macrophage-mediated transformation of fibroblasts into myofibroblasts by inhibiting the activation of the NLRP3 inflammasome in macrophages.Overall,our study identifies a novel anti-inflammatory and anti-cardiac fibrosis role of darapladib in Lp-PLA2 inhibition,elucidating the protective effects of suppressing NLRP3 inflammasome activation.Lp-PLA2 inhibition by darapladib represents a novel therapeutic strategy for hypertensive cardiac damage treatment.