Arginase Activity Mediates Retinal Inflammation in Endotoxin-Induced Uveitis

Zhang, Wenbo; Baban, Babak; Rojas, Modesto; Tofigh, Sohrab; Virmani, S. K.; Patel, Chintan; Behzadian, M. Ali; Romero, Maritza J.; Caldwell, Robert W.; Caldwell, Ruth B.

doi:10.2353/ajpath.2009.081115

Cited by 62 publications

(66 citation statements)

References 57 publications

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“…n ϭ 6 for all groups; *P Ͻ 0.05 vs. control. expression is involved in vascular endothelial dysfunction in a number of disease states, such as hypertension, diabetes, atherosclerosis, ischemia-reperfusion injury, and inflammation (13,14,33,47,48). Despite an array of pathologic conditions associated with elevated arginase function, organs such as the liver require arginase for physiologic function.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of arginase has been reported to decrease blood pressure and improve vascular function of resistance vessels in adult hypertensive rats (2, 13). These findings thus suggest a central role for arginase in diseases in which vascular dysfunction is linked to elevated levels of angiotensin II (ANG II).We and others have found that inflammatory cytokines, reactive oxygen species (ROS), thrombin, LPS, and activation of the RhoA/ROCK pathway can elevate arginase expression and activity (16,26,33,48). RhoA/ROCK has also been indicated as an upstream regulator of mitogen-activated protein kinase (MAPK) family members such as p38 MAPK (22).…”

mentioning

confidence: 88%

“…We and others have found that inflammatory cytokines, reactive oxygen species (ROS), thrombin, LPS, and activation of the RhoA/ROCK pathway can elevate arginase expression and activity (16,26,33,48). RhoA/ROCK has also been indicated as an upstream regulator of mitogen-activated protein kinase (MAPK) family members such as p38 MAPK (22).…”

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confidence: 99%

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Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

Shatanawi¹,

Romero²,

Iddings³

et al. 2011

American Journal of Physiology-Cell Physiology

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Enhanced vascular arginase activity impairs endothelium-dependent vasorelaxation by decreasing l-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production. Elevated angiotensin II (ANG II) is a key component of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated arginase activity. We determined signaling mechanisms by which ANG II increases endothelial arginase function. Results show that ANG II (0.1 μM, 24 h) elevates arginase activity and arginase I expression in bovine aortic endothelial cells (BAECs) and decreases NO production. These effects are prevented by the arginase inhibitor BEC (100 μM). Blockade of ANG II AT(1) receptors or transfection with small interfering RNA (siRNA) for Gα12 and Gα13 also prevents ANG II-induced elevation of arginase activity, but siRNA for Gαq does not. ANG II also elevates active RhoA levels and induces phosphorylation of p38 MAPK. Inhibitors of RhoA activation (simvastatin, 0.1 μM) or Rho kinase (ROCK) (Y-27632, 10 μM; H1152, 0.5 μM) block both ANG II-induced elevation of arginase activity and phosphorylation of p38 MAPK. Furthermore, pretreatment of BAECs with p38 inhibitor SB-202190 (2 μM) or transfection with p38 MAPK siRNA prevents ANG II-induced increased arginase activity/expression and maintains NO production. Additionally, inhibitors of p38 MAPK (SB-203580, 5 μg·kg(-1)·day(-1)) or arginase (ABH, 8 mg·kg(-1)·day(-1)) or arginase gene knockout in mice prevents ANG II-induced vascular endothelial dysfunction and associated enhancement of arginase. These results indicate that ANG II increases endothelial arginase activity/expression through Gα12/13 G proteins coupled to AT(1) receptors and subsequent activation of RhoA/ROCK/p38 MAPK pathways leading to endothelial dysfunction.

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Section: Discussionmentioning

confidence: 99%

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confidence: 88%

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Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

Shatanawi¹,

Romero²,

Iddings³

et al. 2011

American Journal of Physiology-Cell Physiology

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124

114

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“…This is a model for uveitis which is a damaging ocular condition that can lead to severe vision loss and blindness [27]. The model is induced by injecting endotoxin (lipopolysaccharide, LPS) into mice, resulting in an ocular inflammation similar to human acute anterior uveitis such as the breakdown of blood-ocular barrier, increases in retinal inflammatory cytokine production, leukocyte attachment to retinal vessels, and leukocyte infiltration into anterior segments [28–30]. After LPS injection, analysis of 3-nitratyrosine levels demonstrated that endotoxin induced significant nitration of retinal proteins (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

Posttranslational modification of Sirt6 activity by peroxynitrite

Liu

et al. 2015

Free Radical Biology and Medicine

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The mammalian sirtuin 6 (Sirt6) is a site-specific histone deacetylase that regulates chromatin structure and many fundamental biological processes. It inhibits endothelial cell senescence and inflammation, prevents development of cardiac hypertrophy and heart failure, modulates glucose metabolism, and represses tumor growth. The basic molecular mechanisms underlying regulation of Sirt6 enzymatic function are largely unknown. Here we hypothesized that Sirt6 function can be regulated via posttranslational modification, focusing on the role of peroxynitrite, one of the major reactive nitrogen species formed by excessive nitric oxide and superoxide generated during disease processes. We found that incubation of purified recombinant Sirt6 protein with 3-morpholinosydnonimine (SIN-1, a peroxynitrite donor that generates nitric oxide and superoxide simultaneously) increased Sirt6 tyrosine nitration and decreased its intrinsic catalytic activity. Similar results were observed in SIN-1-treated Sirt6 which was overexpressed in HEK293 cells, and on endogenous Sirt6 when human retinal microvascular endothelial cells were treated with SIN-1. To further investigate whether Sirt6 nitration occurs under pathological conditions, we determined Sirt6 nitration and activity in retina using a model of endotoxin-induced retinal inflammation. Our data showed that Sirt6 nitration was increased while its activity was decreased in this model. With mass spectrometry, we identified that tyrosine 257 in Sirt6 was nitrated after SIN-1 treatment. Mutation of tyrosine 257 to phenylalanine caused loss of Sirt6 activity, and abolished SIN-1-induced nitration and decrease in its activity. Mass spectrometry analysis also revealed oxidation of methionine and tryptophan in Sirt6 after SIN-1 treatment. Our results demonstrate a novel regulatory mechanism controlling Sirt6 activity through reactive nitrogen species-mediated post-translational modification under oxidative and nitrosative stress.

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“…Arginase can function as an immunosuppressive factor in the tumor environment (131), in viral (132), or in parasitic infection (133). However, this enzyme has also been identified as an important proinflammatory factor in numerous disease models (134)(135)(136). As inflammation decides the fate of HPV infection and arginase is an important regulator of inflammation and immunity, we investigated the interaction between DNCB-induced inflammation and HPV16.E7 protein in induction of arginase in K14.E7 transgenic mice.…”

Section:  the Aims Of This Study Are Tomentioning

confidence: 99%

Mechanisms of 2,4-Dinitrochlorobenzene-induced acute inflammation in Human Papillomavirus type 16 E7 oncoprotein expressing skin

Tran¹

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Persistent infection with oncogenic human papillomaviruses (HPV), particularly HPV16, is associated with selective expression of two virally encoded proteins (E6 and E7). One action of HPV16.E7 protein is to subvert the innate immune system through the down-regulation of IFNγ pathways, modulation of antigen presentation, and suppression of Toll-like receptor 9 protein.K14.E7 transgenic mice, which express HPV16.E7 oncoprotein within basal keratinocytes under the control of the keratin 14 transcriptional promoter, have been extensively used as a model of HPV oncoprotein-induced immune suppression associated with human squamous cancers, in which only the E6 and E7 genes of the papillomavirus are expressed. It has previously been shown that skin grafts expressing HPV16.E7 oncoprotein are not spontaneously rejected when transplanted onto syngeneic animals, but they are rejected when certain components of the innate immune system are unavailable, confirming that the expression of HPV16.E7 in the epithelium results in the establishment of a local suppressive environment and the subversion of antigen-specific T cells. Therefore, successful strategies targeting HPV-associated cancer need to circumvent or disrupt the local suppressive environment.Topical immunotherapy with immunostimulatory agents has been used clinically to treat cancerous lesions including squamous cell and basal cell carcinoma in immunocompetent and immunosuppressed patients. Topical application of 2,4-dinitrochlorobenzene (DNCB) is an effective therapy for condylomata acuminata caused by HPV infection. DNCB induced the complete clearance of HPV-associated warts in 13/15 patients. However, the use of DNCB for treatment has been discouraged because of its mutagenic potential. The aim of my doctoral research is to understand the mechanism of DNCB-induced inflammation in K14.E7 transgenic mice which has been poorly understood. I hypothesized that understanding how induction of a vigorous acute inflammatory response by DNCB can break the local immune-suppressive environment and restore the effector function of adaptive immunity might lead to more acceptable treatments for persisting HPV infection. In support of this hypothesis, the present study showed that DNCB application along with E7 specific immunization therapy was capable of inducing HPV16.E7 skin graft rejection.Arginase, which metabolizes l-arginine to N-ornithine and urea, has been identified as a crucial regulator of inflammation. As inflammation decides the fate of HPV infection and arginase is an important regulator of inflammation and immunity, I investigated the ii interaction between DNCB-induced inflammation and HPV16.E7 protein in the induction of arginase in K14.E7 transgenic mice. The first part of this study showed that topical DNCB application to skin expressing HPV16.E7 as a transgene induces a hyperinflammatory response, which is not seen in nontransgenic control animals. The E7-associated Taken together, my study suggests that HPV16.E7 protein enhances DNCB associated-prod...

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Arginase Activity Mediates Retinal Inflammation in Endotoxin-Induced Uveitis

Cited by 62 publications

References 57 publications

Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

Posttranslational modification of Sirt6 activity by peroxynitrite

Mechanisms of 2,4-Dinitrochlorobenzene-induced acute inflammation in Human Papillomavirus type 16 E7 oncoprotein expressing skin

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