Selective Up-Regulation of Arginase-1 in Coronary Arteries of Diabetic Patients

Bagi, Zsolt; Fehér, Attila; Dou, Huijuan; Broskova, Zuzana

doi:10.3389/fimmu.2013.00293

Cited by 14 publications

(14 citation statements)

References 60 publications

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“…There is emerging evidence suggesting that the up‐regulation of arginase is a key factor contributing to the development of vascular dysfunction in diabetes mellitus by its reciprocal regulation of NO bioavailability (Bagi et al ., ; Durante, ; Pernow and Jung, ). Accordingly, arginase inhibition has been shown to improve vascular function in experimental and clinical studies of diabetes (Romero et al ., ; Beleznai et al ., ; Grönros et al ., ; Shemyakin et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Tissue‐specific up‐regulation of arginase I and II induced by p38 MAPK mediates endothelial dysfunction in type 1 diabetes mellitus

Pernow

Kiss

Tratsiakovich

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEEmerging evidence suggests a selective up-regulation of arginase I in diabetes causing coronary artery disease; however, the mechanisms behind this up-regulation are still unknown. Activated p38 MAPK has been reported to increase arginase II in various cardiovascular diseases. We therefore tested the role of p38 MAPK in the regulation of arginase I and II expression and its effect on endothelial dysfunction in diabetes mellitus. EXPERIMENTAL APPROACHEndothelial function was determined in septal coronary (SCA), left anterior descending coronary (LAD) and mesenteric (MA) arteries from healthy and streptozotocin-induced diabetic Wistar rats by wire myographs. Arginase activity and protein levels of arginase I, II, phospho-p38 MAPK and phospho-endothelial NOS (eNOS) (Ser 1177 ) were determined in these arteries from diabetic and healthy rats treated with a p38 MAPK inhibitor in vivo. KEY RESULTSDiabetic SCA and MA displayed impaired endothelium-dependent relaxation, which was prevented by arginase and p38 MAPK inhibition while LAD relaxation was not affected. Arginase I, phospho-p38 MAPK and eNOS protein expression was increased in diabetic coronary arteries. In diabetic MA, however, increased expression of arginase II and phospho-p38 MAPK, increased arginase activity and decreased expression of eNOS were observed. All these effects were reversed by p38 MAPK inhibition. CONCLUSIONS AND IMPLICATIONSDiabetes-induced activation of p38 MAPK causes endothelial dysfunction via selective up-regulation of arginase I expression in coronary arteries and arginase II expression in MA. Therefore, regional differences appear to exist in the arginase isoforms contributing to endothelial dysfunction in type 1 diabetes mellitus. BJP

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Section: Discussionmentioning

confidence: 99%

Tissue‐specific up‐regulation of arginase I and II induced by p38 MAPK mediates endothelial dysfunction in type 1 diabetes mellitus

Pernow

Kiss

Tratsiakovich

et al. 2015

British J Pharmacology

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“…Increased A1 expression has been observed in coronary arteries from diabetic patients [27]. Arginase inhibition with L-NOHA restored endothelium-dependent vasodilation in coronary arteries from diabetic patients [28].…”

Section: Arginase In Cardiovascular Diseasementioning

confidence: 99%

Arginase: an old enzyme with new tricks

Caldwell

Toque

Narayanan

2015

Trends in Pharmacological Sciences

262

214

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Arginase has roots in early life forms. It converts L-arginine to urea and ornithine. The former provides protection against NH3; the later serves to stimulate cell growth and other physiological functions. Excessive arginase activity in mammals has been associated with cardiovascular and nervous system dysfunction and diseases. Two relevant aspects of this elevated activity may be involved in these disease states. First, excessive arginase activity reduces the supply of L-arginine needed by nitric oxide (NO) synthase to produce NO. Second, excessive production of ornithine leads to vascular structural problems and neural toxicity. Recent research has identified inflammatory agents and reactive oxygen species (ROS) as drivers of this pathologic elevation of arginase activity and expression. Here we review involvement of arginase in cardiovascular and nervous system dysfunction and discuss potential therapeutic interventions targeting excess arginase.

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“…Both ARG1 and ARG2 proteins were demonstrated in endothelium (for a review, see Pernow and Jung (2013)) and implicated in endothelial dysfunction. Increased Arg1 expression is associated with endothelial dysfunction in diabetic patients (Bagi et al 2013;Beleznai et al 2011) and mice (Romero et al 2012;Toque et al 2013a).…”

Section: Introductionmentioning

confidence: 99%

“…Increased Arg1 expression is associated with endothelial dysfunction in diabetic patients (Bagi et al. ; Beleznai et al. ) and mice (Romero et al.…”

Section: Introductionmentioning

confidence: 99%

Deletion of endothelial arginase 1 does not improve vasomotor function in diabetic mice

et al. 2018

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Endothelial arginase 1 was ablated to assess whether this prevents hyperglycemia‐induced endothelial dysfunction by improving arginine availability for nitric oxide production. Endothelial Arg1‐deficient mice (Arg1‐KOT ie2) were generated by crossing Arg1 fl/fl (controls) with Tie2Cre tg/− mice and analyzed by immunohistochemistry, measurements of hemodynamics, and wire myography. Ablation was confirmed by immunohistochemistry. Mean arterial blood pressure was similar in conscious male control and Arg1‐KOT ie2 mice. Depletion of circulating arginine by intravenous infusion of arginase 1 or inhibition of nitric oxide synthase activity with L‐NG‐nitro‐arginine methyl ester increased mean arterial pressure similarly in control (9 ± 2 and 34 ± 2 mmHg, respectively) and Arg1‐KOT ie2 mice (11 ± 3 and 38 ± 4 mmHg, respectively). Vasomotor responses were studied in isolated saphenous arteries of 12‐ and 34‐week‐old Arg1‐KOT ie2 and control animals by wire myography. Diabetes was induced in 10‐week‐old control and Arg1‐KOT ie2 mice with streptozotocin, and vasomotor responses were studied 10 weeks later. Optimal arterial diameter, contractile responses to phenylephrine, and relaxing responses to acetylcholine and sodium nitroprusside were similar in normoglycemic control and Arg1‐KOT ie2 mice. The relaxing response to acetylcholine was dependent on the availability of extracellular l‐arginine. In the diabetic mice, arterial relaxation responses to endothelium‐dependent hyperpolarization and to exogenous nitric oxide were impaired. The data show that endothelial ablation of arginase 1 in mice does not markedly modify smooth muscle and endothelial functions of a resistance artery under normo‐ and hyperglycemic conditions.

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Selective Up-Regulation of Arginase-1 in Coronary Arteries of Diabetic Patients

Cited by 14 publications

References 60 publications

Tissue‐specific up‐regulation of arginase I and II induced by p38 MAPK mediates endothelial dysfunction in type 1 diabetes mellitus

Tissue‐specific up‐regulation of arginase I and II induced by p38 MAPK mediates endothelial dysfunction in type 1 diabetes mellitus

Arginase: an old enzyme with new tricks

Deletion of endothelial arginase 1 does not improve vasomotor function in diabetic mice

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