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http://purl.uniprot.org/citations/24903103http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/24903103http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.org/dc/terms/identifier"doi:10.1161/circresaha.115.304262"xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Kim J.H."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Cole R.N."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Remaley A.T."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Berkowitz D.E."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Chang F."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Romer L.H."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Bhunia A."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Pandey D."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Bergman Y."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Oh Y.J."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Van Eyk J."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Boronina T.N."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/author"Serbo J."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/date"2014"xsd:gYear
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/name"Circ Res"xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/pages"450-459"xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/title"OxLDL triggers retrograde translocation of arginase2 in aortic endothelial cells via ROCK and mitochondrial processing peptidase."xsd:string
http://purl.uniprot.org/citations/24903103http://purl.uniprot.org/core/volume"115"xsd:string
http://purl.uniprot.org/citations/24903103http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/24903103
http://purl.uniprot.org/citations/24903103http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/24903103
http://purl.uniprot.org/uniprot/#_A0A0N4SUV1-mappedCitation-24903103http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/24903103
http://purl.uniprot.org/uniprot/#_D3Z1T9-mappedCitation-24903103http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/24903103
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