Immune response – NF-kB activation
Innate and adaptive immunity are involved in chronic hypertension and vascular damage. The Ang II/aldosterone/peroxynitrite axis activates the key inflammatory gene transcriptor NF-kB to evoke genomic production of inflammatory cytokines such as Il-1, Il-6 and TNF-a, adhesion molecules (ICAM-1), chemokines, coagulation factors such as von Willebrand’s Factor and IL-18 and plasminogen activator (t-PA) which promote clotting and collagens to promote fibrosis. Aldosterone and Ang II produce a concerted and interactive oxidative and inflammatory cascade by activating most of the cell types found in and around the cardiovascular system, including cardiomyocytes, vascular smooth muscle cells, mesangial cells and podocytes, fibroblasts and immune cells. Aldosterone induces macrophage and T-lymphocyte vascular infiltration through MRs expressed in both of these cell types. Aldosterone produces an M1 proinflammatory phenotype in macrophages through ROS-mediated activation of the NLRP3 inflammasome and can result in Macrophage Activation Syndrome. MR-activated T-lymphocytes infiltrate the cardiovascular system and secrete inflammatory mediators such as interferon-gamma (IFN-y), interleukins and TNF-a. There is a profound increase in CD8+ IFN-y T cells, while regulatory T lymphocytes (Tregs), suppressors of the innate and adaptive immune response, are reduced, priming the system for an acute inflammatory response that is directly associated with COVID-19 severity. (9)