Receptor-Interacting Protein Kinase 3 Inhibition Prevents Cadmium-Mediated Macrophage Polarization and Subsequent Atherosclerosis via Maintaining Mitochondrial Homeostasis

• DOI: 10.3389/fcvm.2021.737652
• Publication Date: 2021-11-08T06:33:51Z
• Authors: Jiexin Zhang; Weijing Feng; Minghui Li; Peier Chen; Xiaodong Ning; Caiwen Ou; Minsheng Chen
• Keywords: Macrophage polarization; Homeostasis

Chronic cadmium (Cd) exposure contributes to the progression of cardiovascular disease (CVD), especially atherosclerosis (AS), but underlying mechanism is unclear. Since mitochondrial homeostasis emerging as a core player in development CVD, it might serve potential linking Cd and AS. In this study, we aimed investigate Cd-mediated AS through macrophage polarization know mechanisms Cd-caused imbalance. vitro, flow cytometry shows that promotes M1-type macrophages, manifested increasing expressions nuclear Factor kappa-light-chain-enhancer activated B (NF-kB) NLR family pyrin domain containing 3 (NLRP3). Mitochondrial tests revealed decreasing membrane mitophage, superoxide (mROS), fission are involved Cd-induced polarization. The upregulated receptor-interacting protein kinase (RIPK3) pseudokinase-mixed lineage domain-like (p-MLKL) were observed. Knocking out RIPK3, followed by expression p-MLKL, improves imbalance which effectively reverses vivo, oil red O staining showed with higher blood significantly aggravates Besides, macrophages observed aortic roots mice immunofluorescence western blot. RIPK3 restored changes above. Finally, administered N-acetyl cysteine (NAC) or division inhibitor-1 (Mdivi-1), decreased mROS fission, inhibited attenuating Cd-treated group. Consequently, pathway impaired homeostasis, resulting pro-inflammatory subsequent provided therapeutic target for