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

Abstract

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 II infusion-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.

• Authors: 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
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 42 Issue 12 Pg. 2016-2032 (Dec 2021) ISSN: 1745-7254 [Electronic] United States
• PMID: 34226664 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to CPS and SIMM.

Chemical References

• Anti-Inflammatory Agents
• Benzaldehydes
• Cardiotonic Agents
• Enzyme Inhibitors
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Oximes
• Angiotensin II
• 1-Alkyl-2-acetylglycerophosphocholine Esterase
• Pla2g7 protein, mouse
• darapladib

Topics

• 1-Alkyl-2-acetylglycerophosphocholine Esterase (antagonists & inhibitors)
• Angiotensin II
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Benzaldehydes (pharmacology, therapeutic use)
• Cardiomegaly (chemically induced, metabolism, prevention & control)
• Cardiotonic Agents (pharmacology, therapeutic use)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Fibrosis (chemically induced, metabolism, prevention & control)
• Heart (drug effects)
• Inflammasomes (metabolism)
• Inflammation (chemically induced, metabolism, prevention & control)
• Macrophages (drug effects)
• Male
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Oximes (pharmacology, therapeutic use)