MKP-1 switches arginine metabolism from nitric oxide synthase to arginase following endotoxin challenge

Nelin, Leif D.; Wang, Xianxi; Zhao, Qun; Chicoine, Louis G.; Young, Tamara L.; Hatch, Dionna M; English, B. Keith; Liu, Yusen

doi:10.1152/ajpcell.00137.2006

Cited by 47 publications

(68 citation statements)

References 37 publications

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“…Recent studies revealed that Mkp-1-deficient mice have inducible nitric oxide synthase-mediated hypotension when challenged with low doses of endotoxin (3). In correlative studies, MKP-1 was shown to be important in switching arginine metabolism from nitric oxide synthase to arginase following LPS challenge of peritoneal macrophages derived from WT or Mkp-1 null mice (36). Other investigators reported increased mortality in Mkp-1 null mice challenged with Gram-positive bacterial infection, through the inactivation of JNK and p38 (56).…”

Section: Discussionmentioning

confidence: 99%

Histone H3 as a novel substrate for MAP kinase phosphatase-1

Kinney

Chandrasekharan

Yang

et al. 2009

American Journal of Physiology-Cell Physiology

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Kinney CM, Chandrasekharan UM, Yang L, Shen J, Kinter M, McDermott MS, DiCorleto PE. Histone H3 as a novel substrate for MAP kinase phosphatase-1. Am J Physiol Cell Physiol 296: C242-C249, 2009. First published November 19, 2008 doi:10.1152/ajpcell.00492.2008.-Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is a nuclear, dual-specificity phosphatase that has been shown to dephosphorylate MAP kinases. We used a "substrate-trap" technique involving a mutation in MKP-1 of the catalytically critical cysteine to a serine residue ("CS" mutant) to capture novel MKP-1 substrates. We transfected the MKP-1 (CS) mutant and control (wild-type, WT) constructs into phorbol 12-myristate 13-acetate (PMA)-activated COS-1 cells. MKP-1-substrate complexes were immunoprecipitated, which yielded four bands of 17, 15, 14, and 10 kDa with the CS MKP-1 mutant but not the WT MKP-1. The bands were identified by mass spectrometry as histones H3, H2B, H2A, and H4, respectively. Histone H3 was phosphorylated, and purified MKP-1 dephosphorylated histone H3 (phospho-Ser-10) in vitro; whereas, histone H3 (phospho-Thr-3) was unaffected. We have previously shown that thrombin and vascular endothelial growth factor (VEGF) upregulated MKP-1 in human endothelial cells (EC). We now show that both thrombin and VEGF caused dephosphorylation of histone H3 (phospho-Ser-10) and histone H3 (phospho-Thr-3) in EC with kinetics consistent with MKP-1 induction. Furthermore, MKP-1-specific small interfering RNA (siRNA) prevented VEGF-and thrombin-induced H3 (phospho-Ser-10) dephosphorylation but had no effect on H3 (phospho-Thr-3 or Thr-11) dephosphorylation. In summary, histone H3 is a novel substrate of MKP-1, and VEGF-and thrombin-induced H3 (phospho-Ser-10) dephosphorylation requires MKP-1. We propose that MKP-1-mediated H3 (phospho-Ser-10) dephosphorylation is a key regulatory step in EC activation by VEGF and thrombin.

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Section: Discussionmentioning

confidence: 99%

Histone H3 as a novel substrate for MAP kinase phosphatase-1

Kinney

Chandrasekharan

Yang

et al. 2009

American Journal of Physiology-Cell Physiology

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“…MKP-1 wild-type and KO mice were kindly provided by Yusen Liu (The Research Institute at Nationwide Children's Hospital, Columbus, OH) (42). Female LDL-R −/− mice (B6.129S7-Ldlr tmIHer /J) were obtained from Jackson Laboratories.…”

Section: Methodsmentioning

confidence: 99%

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Kim¹,

Ullevig

Zamora³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

104

125

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Monocytic adhesion and chemotaxis are regulated by MAPK pathways, which in turn are controlled by redox-sensitive MAPK phosphatases (MKPs). We recently reported that metabolic disorders prime monocytes for enhanced recruitment into vascular lesions by increasing monocytes' responsiveness to chemoattractants. However, the molecular details of this proatherogenic mechanism were not known. Here we show that monocyte priming results in the S-glutathionylation and subsequent inactivation and degradation of MKP-1. Chronic exposure of human THP-1 monocytes to diabetic conditions resulted in the loss of MKP-1 protein levels, the hyperactivation of ERK and p38 in response to monocyte chemoattractant protein-1 (MCP-1), and increased monocyte adhesion and chemotaxis. Knockdown of MKP-1 mimicked the priming effects of metabolic stress, whereas MKP-1 overexpression blunted both MAPK activation and monocyte adhesion and migration induced by MCP-1. Metabolic stress promoted the Sglutathionylation of MKP-1, targeting MKP-1 for proteasomal degradation. Preventing MKP-1 S-glutathionylation in metabolically stressed monocytes by overexpressing glutaredoxin 1 protected MKP-1 from degradation and normalized monocyte adhesion and chemotaxis in response to MCP-1. Blood monocytes isolated from diabetic mice showed a 55% reduction in MKP-1 activity compared with nondiabetic mice. Hematopoietic MKP-1 deficiency in atherosclerosis-prone mice mimicked monocyte priming and dysfunction associated with metabolic disorders, increased monocyte chemotaxis in vivo, and accelerated atherosclerotic lesion formation. In conclusion, we identified MKP-1 as a central redox-sensitive regulator of monocyte adhesion and migration and showed that the loss of MKP-1 activity is a critical step in monocyte priming and the metabolic stress-induced conversion of blood monocytes into a proatherogenic phenotype.M etabolic disorders such as obesity and diabetes are associated with a state of chronic, low-grade inflammation (1, 2), which appears to contribute to the development of micro-and macrovascular complications such as atherosclerosis, nephropathy, and retinopathy (3-5). The cellular and molecular mechanisms involved in chronic inflammation associated with metabolic disorders are not yet fully understood, but the recruitment of blood monocytes to sites of vascular injury appears to play a central and rate-limiting role in all these complications. Metabolic disorders impact blood vessels at multiple levels, including lipid depositions, endothelial injury, and smooth muscle cell proliferation and migration, which individually or in concert initiate monocyte recruitment and promote vascular inflammation (6, 7). However, metabolic disorders also appear to affect blood monocytes directly. A number of studies reported that monocytes both in patients with metabolic disorders and in dyslipidemic or diabetic mice undergo phenotypical and functional changes that may contribute directly to the development and progression of chronic inflammatory vascular diseases (8-13)...

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“…The activation and expression of endothelial arginase II can also be induced by a variety of vascular stimulants, including OxLDL, LPS, TNF-α, IFN-γ, 8-bromocGMP, and hypoxia [7,10,[12][13][14]. Arginase activation/upregulation results in arginase/NOS imbalance, as well as de-creased NO production, and has been demonstrated to contribute to endothelial dysfunction, in a number of diseases/ pathophysiological processes, including aging [4], diabetes [15][16][17], hypertension [18][19][20], and atherosclerosis [14,21].…”

Section: Introductionmentioning

confidence: 99%