State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Acta Pharmacol Sin. 2021 Dec;42(12):2016-2032. doi: 10.1038/s41401-021-00703-7. Epub 2021 Jul 5.
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.
巨噬细胞介导的炎症在高血压性心脏重构中发挥重要作用，而针对心脏炎症的有效药物治疗仍不清楚。脂蛋白相关磷脂酶 A2（Lp-PLA2）通过介导巨噬细胞迁移和激活，促进血管炎症相关疾病的发生。Lp-PLA2 的最先进抑制剂达拉普利在动脉粥样硬化患者的 III 期临床试验中进行了评估。然而，达拉普利在抑制高血压性心脏纤维化中的作用尚不清楚。在使用血管紧张素 II（Ang II）输注诱导的高血压小鼠模型中，我们发现 Pla2g7（Lp-PLA2 的基因）是在高血压性心脏组织中检测到的唯一上调的 PLA2 基因，主要定位于心脏浸润的巨噬细胞中。不出所料，达拉普利显著预防了 Ang II 诱导的心脏纤维化、心室肥厚和心功能障碍，强烈减少了巨噬细胞浸润和炎症反应。RNA 测序显示，达拉普利强烈地下调了与炎症、细胞外基质和增殖相关的基因和信号通路的表达。此外，达拉普利显著降低了 Ang II 输注诱导的核苷酸结合寡聚化结构域样受体含pyrin 结构域 3（NLRP3）和白细胞介素（IL）-1β在心脏组织中的表达，并显著抑制了 caspase-1 的激活。此外，达拉普利通过阻断 NLRP3 炎性小体的激活，改善了 Ang II 刺激的巨噬细胞迁移和 IL-1β 分泌。达拉普利还通过抑制巨噬细胞中 NLRP3 炎性小体的激活，有效阻断了巨噬细胞介导的成纤维细胞向肌成纤维细胞的转化。总之，我们的研究确定了达拉普利抑制 Lp-PLA2 作用的一种新的抗炎和抗心脏纤维化作用，阐明了抑制 NLRP3 炎性小体激活的保护作用。达拉普利抑制 Lp-PLA2 代表了一种治疗高血压性心脏损伤的新的治疗策略。
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