Over-Expression of p190RhoGEF Regulates the Formation of Atherosclerotic Plaques in the Aorta of ApoE−/− Mice via Macrophage Polarization

Abstract

The RhoA-specific guanine nucleotide exchange factor p190RhoGEF has been implicated in the control of cell morphology, focal adhesion formation, and cell motility. Previously, we reported that p190RhoGEF is also active in various immune cells. In this study, we examined whether over-expression of p190RhoGEF could affect atherosclerotic plaque formation in mouse aortae. For that purpose, transgenic (TG) mice over-expressing p190RhoGEF were cross-bred with atherosclerosis-prone apolipoprotein E (ApoE)−/− mice to obtain p190RhoGEF-TG mice with ApoE−/− backgrounds (TG/ApoE−/−). Aortic plaque formation was significantly increased in TG/ApoE mice−/− at 30 to 40 weeks of age compared to that in ApoE−/− mice. Serum concentrations of inflammatory cytokines (IL-6 and TNF-α) were greater in TG/ApoE−/− mice than in ApoE−/− mice at ~40 weeks of age. Furthermore, TG/ApoE−/− mice had a greater proportion of peritoneal macrophages within the M1 subset at 30 to 40 weeks of age, together with higher production of inflammatory cytokines and stronger responses to bacterial lipopolysaccharide than ApoE−/− mice. Collectively, these results highlight a crucial role of enhanced p190RhoGEF expression in atherosclerosis progression, including the activation of pro-inflammatory M1 macrophages.