Regulation of vascular inflammation by aldosterone and histone deacetylases.

摘要

Vascular inflammation is characterized by the accumulation of leukocytes in the vessel wall. Leukocyte trafficking involves a series of discrete steps, including leukocyte rolling, adhesion, diapedesis, and migration. Leukocyte rolling is mediated by selectins and their selectin ligands; leukocyte adherence is mediated by intercellular adhesion molecules and their integrin ligands.;In my thesis research, I have focused on the regulatory mechanisms by which endothelial cells and macrophages are activated to enhance vascular inflammation.;I demonstrate that aldosterone activates endothelial cells. Although aldosterone is thought of as a steroid hormone that regulates blood pressure, it has other pathophysiological effects such as inflammation and fibrosis. However, the mechanisms by which aldosterone induces vascular inflammation are not well understood. Aldosterone rapidly triggers endothelial exocytosis of Weibel-Palade Bodies (WPB), releaseing von Willebrand factor (VWF) and externalizing P-selectin. Aldosterone activates endothelial exocytosis through the mineralocorticoid receptor. The calcium-calmodulin signaling pathway mediates endothelial exocytosis by aldosterone. Aldosterone-induced endothelial exocytosis increases leukocytes adhesion to endothelial cells in vitro.;I also demonstrate that histone deacetylases (HDACs) regulate innate immune signaling by deacetylating MAP kinase phosphatase-1 (MKP-1). Previous studies in my lab identified MKP-1 as a potential acetylation target, but the enzymes acetylating and deacetylating MKP-1 have not yet been identified. I show that macrophages preferentially express HDAC1, 2, 3, and 9. Furthermore, HDAC1, 2, and 3 are associated with MKP-1. HDAC1 deacetylates MKP-1 in vitro. Also, inhibition of HDACs by genetic silencing or by a HDAC1, 2, 3, and 9-specific inhibitor, MS-275, increases MKP-1 acetylation and decreases LPS-induced p38 phosphorylation. Genetic silencing or pharmacological inhibition further decreases LPS-induced iNOS expression and nitrite production from macrophages.;My studies show that aldosterone and HDACs are positive regulators in innate immune signaling.