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Mitochondrial processing peptidases as a target therapy for vascular endothelial dysfunction in atherosclerosis (1146.8)
Author(s) -
Pandey Deepesh,
Bhunia Anil,
Chang Fumin,
Bergman Yehudis,
Kuo Maggie,
Serbo Janna,
Berkowitz Dan,
Romer Lewis
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1146.8
Subject(s) - cytosol , gene knockdown , microbiology and biotechnology , chemistry , mitochondrion , endothelium , internalization , vascular smooth muscle , apoptosis , biochemistry , receptor , biology , endocrinology , enzyme , smooth muscle
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 inhibition, and do not occur at all in LOX‐1 null endothelial cells. In addition, inhibition or siRNA knockdown of the mitochondrial processing peptidase (MPPα) reduces the cytosolic abundance and activity of Arg2 following OxLDL stimulation. Blocking MPP with the biochemical inhibitor O‐phenanthroline also attenuates OxLDL‐mediated changes in HAEC production of ROS and NO. Finally, knockdown of MPPα by adenovirally delivered MPP shRNA interference in isolated mice aortas was associated with improved endothelium‐dependent vascular relaxation as assessed by wire myography following OxLDL exposure, when compared with aortas treated with scrambled shRNA. Hence, inhibition of Arg2 translocation to cytosol by targeting MPP could provide novel therapeutic avenues for the treatment of atherosclerosis and other cardiovascular diseases. Grant Funding Source : NIH, AHA