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

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)-1ß and markedly attenuated caspase-1 activation in cardiac tissues. Furthermore, darapladib ameliorated Ang II-stimulated macrophage migration and IL-1ß 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.

[Suppression effect of Mai Shu on formation of atherosclerotic plaque of apolipoprotein E knock-out mice].

The research aimed to investigate the suppression effect of Mai Shu which contains hawthorn, hippophae, medlar, phytosterols（ß-sitosterol, stigmasterol and campesterol）, ß-glucan and lycopeneon formation of atherosclerotic plaque in apolipoprotein E knock-out (ApoE-/-) mice. Liquid chromatography-ultravioletmass spectrometry（LC-UV-MC） methods were used to analyze the main chemical composition of Mai Shu. Atherosclerotic mice models were established by high-fat diet. The mice were administrated with Mai Shu (1, 2, 4 g·kg-1·d-1) or other contrast materials by intragastric route for 10 weeks continuously. At the end of administration, the blood of mice was collected for tests of the serum total cholesterol（TC）, total triglyceride（TG） and high density lipoprotein cholesterol（HDL-C） level. Atherosclerotic lesions in aorta and aortic root were assessed by calculating the relative area of lesions（oil red O stained）. Intravital fluorescence microscopic system was used to evaluate the leukocyte-endothelial adhesion in mesenteric artery of mice by detecting the rolling velocity of white blood cells（WBC）. Collagenous fibers and macrophages in lesions were detected by sirius red staining and immunological histological chemistry to evaluate the atherosclerotic plaque stability. Results showed that Mai Shu contains various flavonoids（9.5%）, phytosterols（23.8%） and polysaccharides（8.9%）. The serum lipid level of model animals was significantly higher than the control animals. Serum TC level was decreased by Mai Shu (4 g·kg-1, P < 0.001) compared to the untreated model. Serum TG level was reduced by Mai Shu (1, 2, 4 g·kg-1) compared to model（P < 0.01）. Area of atherosclerotic lesions in aorta and aortic root was decreased in Mai Shu group (aorta: 1 g·kg-1, P < 0.05; 2 g·kg-1, P < 0.01; 4 g·kg-1, P < 0.001; aortic root: 2, 4 g·kg-1, P < 0.01). Rolling velocity of white blood cells of Mai Shu (4 g·kg-1, P < 0.001) group was increased over the untreated model. Collagenous fibers in lesions were observationally increased by Mai Shu (1, 2 g·kg-1) and macrophages were decreased (2, 4 g·kg-1) compared to model. These results demonstrate that Mai Shu can obviously decrease the serum lipid levels and the risk of leukocyte-endothelial adhesion in ApoE-/- mice. The effect of Mai Shu may be associated with the decrease of macrophages in plaque.