Abstract 223: Monocytes/macrophages Are Sensitized to Secondary Oxidative Insult by Cardiovascular Toxic Drugs via the P90rsk-erk5 S496 Phosphorylation Pathway, Aggrandizing Atherosclerotic Plaque Formation

Abstract

Increased cardiovascular (CV) events in HIV patients and cancer survivors and the fact that combination antiretroviral therapy (cART) and chemotherapy induce similar unwanted CV effects are becoming evident, but the reason for this is unclear. In this study, we examined the role of p90RSK in the CV toxicity of cART and anti-cancer drugs. The level of p90RSK activation by H2O2 was higher in peripheral monocytes from cART-treated patients than in those from untreated patients. Multiple linear regression analysis involving HIV+/-, Reynolds CV risk score, and basal p90RSK activation revealed HIV+/- and basal p90RSK activation to be strong determinants for plaque formation when adjusted for other independent variables. In murine macrophages most of the cART and several chemotherapy agents activated p90RSK and reduced antioxidant molecule expression and telomere (TL) lengths. p90RSK-mediated ERK5 S496 phosphorylation inhibited transcriptional activity of ERK5 and NRF2, decreasing efferocytosis, antioxidant production and TL lengths. NRF2 activator normalized cART-induced sensitization of p90RSK to H2O2. Lastly, we generated myeloid cells-specific wild type (WT) and dominant negative (DN) p90RSK transgenic mice, and ERK5 S496A knock-in mice, crossed with Ldlr-/- mice or treated with a single injection of adeno-associated virus vector (AAV) encoding a gain-of-function mutant of PCSK9 and fed a high fat diet. Our animal studies showed the crucial role of p90RSK-mediated ERK5 S496 phosphorylation in suppressing effecrocytosis and antioxidant production, and up-regulating senescence and inflammation-related molecules expression, leading to atherogenesis. Our results taken together show that p90RSK is activated by anti-HIV and anti-cancer drugs, and this activation sensitizes the monocyte/macrophages to the secondary oxidative insult by reducing NRF2 transcriptional activity and TL length. The p90RSK activation also reduces macrophage efferocytosis and antioxidant capacity, and increases inflammation and senescence via up-regulating ERK5 S496 phosphorylation, thereby accelerating atherosclerosis. Monocyte/macrophage p90RSK-ERK5 S496 phosphorylation could be a good target to prevent drugs-induced CV diseases.