OxLDL triggers retrograde translocation of arginase2 in aortic endothelial cells via ROCK and mitochondrial processing peptidase

Circ Res. 2014 Aug 1;115(4):450-9. doi: 10.1161/CIRCRESAHA.115.304262. Epub 2014 Jun 5.


Rationale: Increased arginase activity contributes to endothelial dysfunction by competition for l-arginine substrate and reciprocal regulation of nitric oxide synthase (NOS). The rapid increase in arginase activity in human aortic endothelial cells exposed to oxidized low-density lipoprotein (OxLDL) is consistent with post-translational modification or subcellular trafficking.

Objective: To test the hypotheses that OxLDL triggers reverse translocation of mitochondrial arginase 2 (Arg2) to cytosol and Arg2 activation, and that this process is dependent on mitochondrial processing peptidase, lectin-like OxLDL receptor-1 receptor, and rho kinase.

Methods and results: OxLDL-triggered translocation of Arg2 from mitochondria to cytosol in human aortic endothelial cells and in murine aortic intima with a concomitant rise in arginase activity. All of these changes were abolished by inhibition of mitochondrial processing peptidase or by its siRNA-mediated knockdown. Rho kinase inhibition and the absence of the lectin-like OxLDL receptor-1 in knockout mice also ablated translocation. Aminoterminal sequencing of Arg2 revealed 2 candidate mitochondrial targeting sequences, and deletion of either of these confined Arg2 to the cytoplasm. Inhibitors of mitochondrial processing peptidase or lectin-like OxLDL receptor-1 knockout attenuated OxLDL-mediated decrements in endothelial-specific NO production and increases in superoxide generation. Finally, Arg2(-/-) mice bred on an ApoE(-/-) background showed reduced plaque load, reduced reactive oxygen species production, enhanced NO, and improved endothelial function when compared with ApoE(-/-) controls.

Conclusions: These data demonstrate dual distribution of Arg2, a protein with an unambiguous mitochondrial targeting sequence, in mammalian cells, and its reverse translocation to cytoplasm by alterations in the extracellular milieu. This novel molecular mechanism drives OxLDL-mediated arginase activation, endothelial NOS uncoupling, endothelial dysfunction, and atherogenesis.

Keywords: arginase; atherosclerosis; mitochondria; mitochondrial processing peptidase; nitric oxide synthase type III; oxidized low density lipoprotein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Aorta / drug effects
  • Aorta / enzymology*
  • Aorta / pathology
  • Aorta / physiopathology
  • Aortic Diseases / enzymology
  • Aortic Diseases / genetics
  • Aortic Diseases / pathology
  • Aortic Diseases / physiopathology
  • Aortic Diseases / prevention & control
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Arginase / genetics
  • Arginase / metabolism*
  • Atherosclerosis / enzymology
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Atherosclerosis / physiopathology
  • Atherosclerosis / prevention & control
  • Cells, Cultured
  • Cytosol / enzymology
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology*
  • Enzyme Activation
  • Humans
  • Lipoproteins, LDL / metabolism*
  • Male
  • Metalloendopeptidases / antagonists & inhibitors
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / enzymology*
  • Molecular Sequence Data
  • Protein Kinase Inhibitors / pharmacology
  • Protein Transport
  • RNA Interference
  • Scavenger Receptors, Class E / deficiency
  • Scavenger Receptors, Class E / genetics
  • Signal Transduction
  • Time Factors
  • Transfection
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism*


  • Apolipoproteins E
  • Lipoproteins, LDL
  • Olr1 protein, mouse
  • Protein Kinase Inhibitors
  • Scavenger Receptors, Class E
  • oxidized low density lipoprotein
  • rho-Associated Kinases
  • Metalloendopeptidases
  • mitochondrial processing peptidase
  • ARG2 protein, human
  • Arg2 protein, mouse
  • Arginase