Background: Increased incidence of cardiovascular disease (CVD) in HIV patients has been established, but the consequence of anti-HIV therapies in CVD is unclear. The activation of p90RSK in endothelial cells is a critical event in atherosclerosis, but its role in macrophage is unknown.
Hypothesis: macrophage p90RSK plays a role in anti-HIV drug-induced CVD and atherosclerosis.
Methods and Results: In macrophages, efferocytosis-related signaling was upregulated and inflammatory gene expression was down-regulated in a p90RSK activity-dependent manner. Using Lysm-Cre dominant negative (DN) p90RSK transgenic mice in LDLR-/- background fed a high-cholesterol diet, we found that p90RSK activation increases plaque formation, inducing pro-atherogenic phenotypes and enhancing M1 polarization. Every cART regimen we tested, except backbone regimen, activated macrophage p90RSK, reduced efferocytosis, and increased M1-type related gene expression. In human, peripheral monocytes were isolated from HIV infected individuals on stable cART for at least 1 year and with viral load ≤50 copies/mL and also from HIV negative and non-cART treated controls matched for age, gender, environment and Reynolds CVD risk score. We found significantly increased p90RSK activation in the cART-treated group, and additional treatment of low dose of H2O2 (200 nM) accelerated p90RSK activation more in the macrophage isolated from cART-treated patients than those in control patients in vitro.
Conclusions: Our results demonstrate that p90RSK is robustly activated by anti-HIV drug treatments known to be a high CVD risk. This activation culminates in reduced activity of macrophage efferocytosis, thereby accelerating atherosclerotic plaque formation. Monocyte/macrophage p90RSK can be a good target and an excellent biological marker to prevent and predict drugs-induced CVD.