Arginase 1 contributes to diminished coronary arteriolar dilation in patients with diabetes

Beleznai, Timea; Fehér, Attila; Spielvogel, David; Lansman, Steven L.; Bagi, Zsolt

doi:10.1152/ajpheart.00831.2010

Cited by 77 publications

(80 citation statements)

References 41 publications

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“…12 Of further importance is the observation that arginase I is upregulated in coronary arterioles of patients with type 2 diabetes mellitus, contributing to a reduced NO production in vitro. 13 However, no previous study has evaluated the functional importance of arginase activity for endothelial function in patients with atherosclerosis and type 2 diabetes mellitus in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…This is supported by a recent study showing that arginase I is upregulated in coronary arterioles of patients with type 2 diabetes mellitus, contributing to a reduced NO production in vitro. 13 However, whether arginase activity contributes to endothelial dysfunction in patients with CAD and diabetes mellitus in vivo is unknown. Thus, the main objective of the current study was to test the hypothesis that arginase contributes to the occurrence of endothelial dysfunction and that arginase blockade improves endothelial function in patients with CAD and type 2 diabetes mellitus.…”

Section: Clinical Perspective On P 2950mentioning

confidence: 99%

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Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus

et al. 2012

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Background— Endothelial dysfunction plays an important role in the early development of atherosclerosis and vascular complications in type 2 diabetes mellitus. Increased expression and activity of arginase, metabolizing the nitric oxide substrate l -arginine, may result in reduced production of nitric oxide and thereby endothelial dysfunction. We hypothesized that inhibition of arginase activity improves endothelial function in patients with coronary artery disease (CAD) and type 2 diabetes mellitus. Methods and Results— Three groups of subjects were included: 16 patients with CAD, 16 patients with CAD and type 2 diabetes mellitus (CAD+Diabetes), and 16 age-matched healthy control subjects. Forearm endothelium-dependent and endothelium-independent vasodilatation were assessed with venous occlusion plethysmography before and during intra-arterial infusion of the arginase inhibitor N ω -hydroxy-nor- l -arginine (nor-NOHA; 0.1 mg/min). Nor-NOHA was also coinfused with the nitric oxide synthase inhibitor ( N G -monomethyl L-arginine). The expression of arginase was determined in the internal mammary artery of patients undergoing bypass surgery. Nor-NOHA markedly increased endothelium-dependent vasodilatation (up to 2-fold) in patients with CAD+Diabetes and CAD ( P <0.001) but not in the control group. N G -monomethyl L-arginine completely inhibited the increase in endothelium-dependent vasodilatation induced by nor-NOHA. Endothelium-independent vasodilatation was slightly improved by nor-NOHA in the CAD+Diabetes group. Arginase I was expressed in vascular smooth muscle cells and endothelial cells, and arginase II was expressed in endothelial cells of patients with and without diabetes mellitus. Conclusions— Arginase inhibition markedly improves endothelial function in patients with CAD and type 2 diabetes mellitus suggesting that increased arginase activity is a key factor in the development of endothelial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Perspective On P 2950mentioning

confidence: 99%

Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus

et al. 2012

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“…We (25) have also shown that STZ-induced diabetesinduced impairment of coronary vasorelaxation to ACh in rats was correlated with increases in ROS, arginase activity, and AI expression in the aorta. Additionally, a recent study (2) of diabetic human coronary arterioles demonstrated the involvement of upregulated AI in reduced NO production and vasodilation. Together, these results suggest that the involvement of arginase isoforms in vascular dysfunction varies depending on the model and disease condition.…”

Section: Vascular Functionmentioning

confidence: 97%

Diabetes-induced vascular dysfunction involves arginase I

Romero¹,

Iddings²,

Platt³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Arginase can cause vascular dysfunction by competing with nitric oxide synthase for L-arginine and by increasing cell proliferation and collagen formation, which promote vascular fibrosis/stiffening. We have shown that increased arginase expression/activity contribute to vascular endothelial cell (EC) dysfunction. Here, we examined the roles of the two arginase isoforms, arginase I and II (AI and AII, respectively), in this process. Experiments were performed using streptozotocin-induced diabetic mice: wild-type (WT) mice and knockout mice lacking the AII isoform alone (AI ϩ/ϩ AII Ϫ/Ϫ ) or in combination with partial deletion of AI (AI ϩ/Ϫ AII Ϫ/Ϫ ). EC-dependent vasorelaxation of aortic rings and arterial fibrosis and stiffness were assessed in relation to arginase activity and expression. Diabetes reduced mean ECdependent vasorelaxation markedly in diabetic WT and AI ϩ/ϩ AII mice. In diabetic WT and AI ϩ/ϩ AII Ϫ/Ϫ mice, aortic arginase activity and AI expression were significantly increased compared with control mice, but neither parameter was altered in AI ϩ/Ϫ AII Ϫ/Ϫ mice. In summary, AI ϩ/Ϫ AII Ϫ/Ϫ mice exhibit better EC-dependent vasodilation and less vascular stiffness and coronary fibrosis compared with diabetic WT and AI ϩ/ϩ AII Ϫ/Ϫ mice. These data indicate a major involvement of AI in diabetes-induced vascular dysfunction. fibrosis; oxidative stress; vascular stiffness IN VASCULAR ENDOTHELIAL CELLS (ECs), nitric oxide (NO) synthase (NOS) uses L-arginine to produce NO, which maintains blood flow and reduces inflammation (21,22). Reduced availability of L-arginine to NOS and the resultant reduction of NO production have been implicated in the vascular dysfunction associated with diabetes and other cardiovascular disease states. Acute L-arginine supplementation can prevent or reverse EC dysfunction and restore EC-dependent vasodilation in diabetes (1, 31). Reduced availability of L-arginine for NOS can occur via increased activity or expression of arginase, an enzyme that competes with NOS for L-arginine, producing ornithine and urea.Two isoforms of arginase exist in mammals, arginase I and II (AI and AII, respectively) (8, 23). AI, which is located in the cytoplasm, is expressed most abundantly in liver, whereas AII is a mitochondrial enzyme expressed primarily in the kidney. Both AI and AII have been found in EC populations (11, 34). During diabetes, impaired vascular function is closely associated with oxidative stress and inflammation (12, 28), both of which have been associated with elevated arginase activity and expression (4, 18).Enhanced arginase activity appears to be involved in conditions characterized by vascular endothelial dysfunction (VED), such as diabetes, pulmonary hypertension, ischemia-reperfusion, and aging (5,19,29,33, 42). Additionally, high chronic L-arginine intake can induce arginase expression/activity, thereby inducing vascular dysfunction (20,21,30,35). Competition between arginase and NOS for their common substrate, arginine, suggests a cause-and-effect relationship in which...

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“…24 Moreover, coronary endothelial function is disrupted in type 2 diabetic patients and rodents. 27,28 The vascular redox status greatly contributes to endothelial homeostasis by modulating the function of TRP channels. 29 Mitochondrial ROS play an important role in the progression of coronary atherosclerosis and subsequent myocardial ischemic injury.…”

Section: Impairment Of Protective Targets Increases Mitochondrial Rosmentioning

confidence: 99%

Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1–Mediated Protein Kinase A/Uncoupling Protein 2 Pathway

Xiong

Wang

et al. 2016

Hypertension

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Arginase 1 contributes to diminished coronary arteriolar dilation in patients with diabetes

Cited by 77 publications

References 41 publications

Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus

Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus

Diabetes-induced vascular dysfunction involves arginase I

Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1–Mediated Protein Kinase A/Uncoupling Protein 2 Pathway

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