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Free keywords:
G-PROTEINS; CHOLESTEROL EFFLUX; NATURAL IGM; ATHEROSCLEROSIS; CELLS;
RHO; INFLAMMATION; EXPRESSION; MIGRATION; RACHematology; Cardiovascular System & Cardiology; atherosclerosis; gene expression; GTP-binding proteins; macrophages;
signal transduction;
Abstract:
Objectives Monocyte/macrophage recruitment and activation at vascular predilection sites plays a central role in the pathogenesis of atherosclerosis. Heterotrimeric G proteins of the G(12/13) family have been implicated in the control of migration and inflammatory gene expression, but their function in myeloid cells, especially during atherogenesis, is unknown.
Approach and Results Mice with myeloid-specific deficiency for G(12/13) show reduced atherosclerosis with a clear shift to anti-inflammatory gene expression in aortal macrophages. These changes are because of neither altered monocyte/macrophage migration nor reduced activation of inflammatory gene expression; on the contrary, G(12/13)-deficient macrophages show an increased nuclear factor-B-dependent gene expression in the resting state. Chronically increased inflammatory gene expression in resident peritoneal macrophages results in myeloid-specific G(12/13)-deficient mice in an altered peritoneal micromilieu with secondary expansion of peritoneal B1 cells. Titers of B1-derived atheroprotective antibodies are increased, and adoptive transfer of peritoneal cells from mutant mice conveys atheroprotection to wild-type mice. With respect to the mechanism of G(12/13)-mediated transcriptional control, we identify an autocrine feedback loop that suppresses nuclear factor-B-dependent gene expression through a signaling cascade involving sphingosine 1-phosphate receptor subtype 2, G(12/13), and RhoA.
Conclusions Together, these data show that selective inhibition of G(12/13) signaling in macrophages can augment atheroprotective B-cell populations and ameliorate atherosclerosis.
