OxLDL Triggers Retrograde Translocation of Arginase2 in Aortic Endothelial Cells via ROCK and Mitochondrial Processing Peptidase

Pandey, Deepesh; Bhunia, Anil K.; Oh, Young Jun; Chang, Fumin; Bergman, Yehudit; Kim, Jae Hyung; Serbo, Janna; Boronina, Tatiana; Cole, Robert N.; Eyk, Jennifer E. Van; Remaley, Alan T.; Berkowitz, Dan E.; Romer, Lewis H.

doi:10.1161/circresaha.115.304262

Cited by 84 publications

(70 citation statements)

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“…29,[101][102][103][104][105] Major causes of l-arginine steal in the blood vessel wall include increased ROS production and activation of Rho-kinase that stimulates both mitochondrial processing peptidase (promoting translocation of arginase from mitochondria to the cytosol and hence increasing its activity) and p38 mitogen-activated PK (phosphorylating transcription factors [activating transcription factor-2 and c-Jun] upregulating the expression and activity of the enzyme); conversely, inhibition of arginases improves endothelium-dependent, NO-mediated dilatations/ relaxations when they are impaired because of upregulation of these enzymes. [100][101][102][103][104][105][106][107][108][109] Another sink for l-arginine can be the induction of iNOS, which is minimally present under physiological conditions, but when expressed/present during infection, chronic inflammation, and in tumors, continuously produces large amounts of NO, thus competing with eNOS for the common substrate and accelerating S-nitrosylation of the enzyme ( Figure 5). …”

Section: Abnormal Coupling Of Endothelial Cell Membrane Receptorsmentioning

confidence: 99%

Thirty Years of Saying NO

Vanhoutte

Zhao

et al. 2016

Circulation Research

331

156

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T he historical demonstration by Furchgott and Zawadzki 1 that removal of the endothelium abrogates the in vitro vasodilator effect of acetylcholine has led to the identification 30 years ago of nitric oxide (NO) as a major endogenous local regulator of vascular tone. [2][3][4][5][6][7][8][9][10] When the ability of endothelial cells to produce NO is blunted, the ensuing vascular dysfunction sets the stage for the occurrence of cardiovascular disease in general, and atherosclerosis in particular. [11][12][13][14][15] This review focuses, stepby-step, on the bioavailability (production, action, and disposition) of endothelium-derived NO as local regulator of vascular tone in health and disease. Obviously, there is much more than NO in the control of the degree of contraction of underlying vascular smooth muscle cells exerted by the endothelial cells. Indeed, they generate also prostacyclin and hyperpolarizing signals (initiating endothelium-dependent hyperpolarization [EDH] and thus relaxation) and produce vasoconstrictor mediators (endothelium-derived contracting factors and the peptide endothelin-1); those have been discussed elsewhere in detail. 15-22 Endothelial Sources of NO NO SynthaseThree NO synthase (NOS) isozymes, which are encoded by different genes, catalyze the production of NO from l-arginine: neuronal NOS (or NOS-1), cytokine-inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3).6,23-25 Although iNOS can be induced (by lipopolysaccharides and inflammatory cytokines) and neuronal NOS can be present in the blood vessel

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Section: Abnormal Coupling Of Endothelial Cell Membrane Receptorsmentioning

confidence: 99%

Thirty Years of Saying NO

Vanhoutte

Zhao

et al. 2016

Circulation Research

331

156

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“…Although arginase II participates in the endothelial dysfunction, the mechanism through which endothelial NOS activity is regulated remains unclear. However, a novel mechanism showed that oxidized low‐density lipoprotein triggered translocation of arginase II from mitochondria to the cytoplasm via mitochondrial processing peptidase with a simultaneous increase in arginase activity that drove endothelial nitric oxide synthase (eNOS) uncoupling by depleting the substrate pool available for NO biosynthesis 17. Similarily, we also showed that an arginase inhibitor‐enhanced eNOS phosphorylation at Ser117718 and arginase II inhibition improved the loss of mitochondrial membrane potential by a Ca 2+ ‐dependent mechanism and prevented mitochondrial reactive oxygen species (ROS) production 19…”

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confidence: 99%

Arginase II Contributes to the Ca ²⁺ /CaMKII/eNOS Axis by Regulating Ca ²⁺ Concentration Between the Cytosol and Mitochondria in a p32‐Dependent Manner

Koo

Hwang

et al. 2018

JAHA

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BackgroundArginase II activity contributes to reciprocal regulation of endothelial nitric oxide synthase (eNOS). We tested the hypotheses that arginase II activity participates in the regulation of Ca2+/Ca2+/calmodulin‐dependent kinase II/eNOS activation, and this process is dependent on mitochondrial p32.Methods and ResultsDownregulation of arginase II increased the concentration of cytosolic Ca2+ ([Ca2+]c) and decreased mitochondrial Ca2+ ([Ca2+]m) in microscopic and fluorescence‐activated cell sorting analyses, resulting in augmented eNOS Ser1177 phosphorylation and decreased eNOS Thr495 phosphorylation through Ca2+/Ca2+/calmodulin‐dependent kinase II. These changes were observed in human umbilical vein endothelial cells treated with small interfering RNA against p32 (sip32). Using matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry, fluorescence immunoassay, and ion chromatography, inhibition of arginase II reduced the amount of spermine, a binding molecule, and the release of Ca2+ from p32. In addition, arginase II gene knockdown using small interfering RNA and knockout arginase II‐null mice resulted in reduced p32 protein level. In the aortas of wild‐type mice, small interfering RNA against p32 induced eNOS Ser1177 phosphorylation and enhanced NO‐dependent vasorelaxation. Arginase activity, p32 protein expression, spermine amount, and [Ca2+]m were increased in the aortas from apolipoprotein E (ApoE−/−) mice fed a high‐cholesterol diet, and intravenous administration of small interfering RNA against p32 restored Ca2+/Ca2+/calmodulin‐dependent kinase II‐dependent eNOS Ser1177 phosphorylation and improved endothelial dysfunction. The effects of arginase II downregulation were not associated with elevated NO production when tested in aortic endothelia from eNOS knockout mice.ConclusionsThese data demonstrate a novel function of arginase II in regulation of Ca2+‐dependent eNOS phosphorylation. This novel mechanism drives arginase activation, mitochondrial dysfunction, endothelial dysfunction, and atherogenesis.

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“…Arginase 2 Translocation by OxLDL (p 450) 44 Blocking arginase 2 activity reduces severity of atherosclerosis, report Pandey et al…”

Section: Williams and The Editors "In This Issue" Anthology E109mentioning

confidence: 99%

Circulation Research “In This Issue” Anthology

Williams¹

2015

Circulation Research

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1 MicroRNA-181b inhibits vascular inflammation and atherosclerosis in mice, report Sun et al.Atherosclerosis is a chronic inflammatory vascular disease that is in part driven by the activation of the transcription factor NF-κB. In vascular endothelial cells, oxidized low-density lipoproteins, angiotensin II and other pro-atherogenic factors activate NF-κB. These factors promote the transfer of NFkB from the cytoplasm to the nucleus where it increases the transcription of pro-inflammatory genes. Recently, miR-181b was found to repress importin-α3, the protein responsible for transferring NF-κB to the nucleus. But whether this miR could actually suppress atherosclerosis was unknown. This prompted Sun and colleagues to inject atherosclerosis-prone mice with a version of miR-181b. They found that miR-181b reduced NF-κB activity as well as the expression of importin-α in the aortic arches of the mice. Importantly, atherosclerotic lesion formation was also reduced, and the lesions contained fewer macrophages and T cells. Interestingly, the team also found that patients with coronary artery disease had reduced levels of miR-181b in their blood. Taken together these results indicate that increasing miR-181b levels in patients could be a potential therapy for diminishing atherogenesis. A non-fatal heart attack often leads to progressive tissue damage that results in heart failure. Indeed, despite recent advances, Lasting Effects of AAV1/SERCA2a in Heart Failure

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OxLDL Triggers Retrograde Translocation of Arginase2 in Aortic Endothelial Cells via ROCK and Mitochondrial Processing Peptidase

Cited by 84 publications

References 48 publications

Thirty Years of Saying NO

Thirty Years of Saying NO

Arginase II Contributes to the Ca ²⁺ /CaMKII/eNOS Axis by Regulating Ca ²⁺ Concentration Between the Cytosol and Mitochondria in a p32‐Dependent Manner

Circulation Research “In This Issue” Anthology

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OxLDL Triggers Retrograde Translocation of Arginase2 in Aortic Endothelial Cells via ROCK and Mitochondrial Processing Peptidase

Cited by 84 publications

References 48 publications

Thirty Years of Saying NO

Thirty Years of Saying NO

Arginase II Contributes to the Ca 2+ /CaMKII/eNOS Axis by Regulating Ca 2+ Concentration Between the Cytosol and Mitochondria in a p32‐Dependent Manner

Circulation Research “In This Issue” Anthology

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Arginase II Contributes to the Ca ²⁺ /CaMKII/eNOS Axis by Regulating Ca ²⁺ Concentration Between the Cytosol and Mitochondria in a p32‐Dependent Manner