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.

Integrated adrenal and testicular metabolomics revealed the protective effects of Guilingji on the Kidney-Yang deficiency syndrome rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Guilingji (GLJ) is a well-known traditional Chinese medicine (TCM) prescription for the treatment of Kidney-Yang deficiency syndrome (KYDS). AIM OF THE STUDY: This study aimed to address the protective effects of GLJ against KYDS in rats with pharmacodynamic indicators and target tissues (adrenal gland and testis) metabolomics. MATERIALS AND METHODS: The rats were injected intraperitoneally (i.p) hydrocortisone to simulate KYDS and administered orally of GLJ for 30 days. Traditional pharmacodynamic indicators (body weight, behavioral indicators, biochemical parameters and histological examination) were performed to evaluate the efficacy of GLJ. Furthermore, adrenal gland and testis metabolic profiles obtained by UHPLC-Q Exactive Orbitrap-MS coupled with multivariate analysis were conducted to explore the metabolic regulation mechanism of GLJ. RESULTS: After administration of GLJ, the weight, levels of behavioral indicators and biochemical parameters of rats were increased compared with those of the model group, and the abnormalities of morphology in adrenal and testicular tissues were improved. Furthermore, GLJ had recovering effects via the adjustment of vitamins metabolism, which was accompanied by lipids metabolism, amino acid metabolism and nucleotides metabolism. CONCLUSIONS: The study firstly integrated the target tissues metabolic profiles, which were complementary, and GLJ had protective effects on KYDS rats via the regulation of steroid hormone biosynthesis, oxidant-antioxidant balance and energy acquisition.