Mitochondrial processing peptidases as a target therapy for vascular endothelial dysfunction in atherosclerosis (1146.8)

Oxidized Low density lipoprotein (OxLDL) acts via its receptor LOX-1 and elicits endothelial dysfunction that is considered a hallmark for initiation and progression of atherosclerosis. However, the precise mechanism by which this occurs is still unclear and is the main focus of current study. Our time course, subcellular fractionation, and immunofluorescence data support our hypothesis that Arg2 is a dual-targeted single gene and single mRNA product found in both mitochondrial and cytosolic fractions of HAEC - a novel pattern of effector system activation in mammalian vascular injury. These data indicate that OxLDL-mediated activation of Arg2 in HAEC and in mouse aortic intima occurs via post-translational modification and subcellular translocation of pre-existing pools of Arg2 from mitochondria to the cytosol. Accumulated Arginase 2 in cytosol diminishes the concentration of cytosolic L-arginine and leads to eNOS uncoupling. OxLDL-evoked changes in cytosolic Arg2 activity are muted by Rho-kinase inhibit...