Diabetes-induced vascular dysfunction involves arginase

Maritza Josefina Romero Lucas, Jennifer A. Iddings, Daniel H. Platt, M. Irfan Ali, Stephen D. Cederbaum, David W Stepp, Ruth B Caldwell, Robert William Caldwell

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Arginase can cause vascular dysfunction by competing with nitric oxide synthase for L-argi-nine 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 +/+AII -/-) or in combination with partial deletion of AI (AI +/+AII -/-). EC-dependent vasorelaxation of aortic rings and arterial fibrosis and stiffness were assessed in relation to arginase activity and expression. Diabetes reduced mean EC-dependent vasorelaxation markedly in diabetic WT and AI +/+AII -/- aortas (53% and 44% vs. controls, respectively) compared with a 27% decrease in AI +/+AII -/- vessels. Coronary fibrosis was also increased in diabetic WT and AI +/+AII -/- mice (1.9- and 1.7-fold vs. controls, respectively) but was not altered in AI +/+AII -/- diabetic mice. Carotid stiffness was increased by 142% in WT diabetic mice compared with 51% in AI +/+AII -/- mice and 19% in AI +/+AII -/- mice. In diabetic WT and AI +/+AII -/- mice, aortic arginase activity and AI expression were significantly increased compared with control mice, but neither parameter was altered in AI +/~AII -/- mice. In summary, AI +/~AII -/- mice exhibit better EC-dependent vasodilation and less vascular stiffness and coronary fibrosis compared with diabetic WT and AI +/+AII -/- mice. These data indicate a major involvement of AI in diabetes-induced vascular dysfunction.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume302
Issue number1
DOIs
StatePublished - Jan 1 2012

Fingerprint

Arginase
Blood Vessels
Fibrosis
Endothelial Cells
Vasodilation
Vascular Stiffness
Protein Isoforms
Streptozocin
Knockout Mice
Nitric Oxide Synthase
Aorta
Collagen

Keywords

  • Fibrosis
  • Oxidative stress
  • Vascular stiffness

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Diabetes-induced vascular dysfunction involves arginase. / Romero Lucas, Maritza Josefina; Iddings, Jennifer A.; Platt, Daniel H.; Irfan Ali, M.; Cederbaum, Stephen D.; Stepp, David W; Caldwell, Ruth B; Caldwell, Robert William.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 302, No. 1, 01.01.2012.

Research output: Contribution to journalArticle

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abstract = "Arginase can cause vascular dysfunction by competing with nitric oxide synthase for L-argi-nine 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 +/+AII -/-) or in combination with partial deletion of AI (AI +/+AII -/-). EC-dependent vasorelaxation of aortic rings and arterial fibrosis and stiffness were assessed in relation to arginase activity and expression. Diabetes reduced mean EC-dependent vasorelaxation markedly in diabetic WT and AI +/+AII -/- aortas (53{\%} and 44{\%} vs. controls, respectively) compared with a 27{\%} decrease in AI +/+AII -/- vessels. Coronary fibrosis was also increased in diabetic WT and AI +/+AII -/- mice (1.9- and 1.7-fold vs. controls, respectively) but was not altered in AI +/+AII -/- diabetic mice. Carotid stiffness was increased by 142{\%} in WT diabetic mice compared with 51{\%} in AI +/+AII -/- mice and 19{\%} in AI +/+AII -/- mice. In diabetic WT and AI +/+AII -/- mice, aortic arginase activity and AI expression were significantly increased compared with control mice, but neither parameter was altered in AI +/~AII -/- mice. In summary, AI +/~AII -/- mice exhibit better EC-dependent vasodilation and less vascular stiffness and coronary fibrosis compared with diabetic WT and AI +/+AII -/- mice. These data indicate a major involvement of AI in diabetes-induced vascular dysfunction.",
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AU - Platt, Daniel H.

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AU - Stepp, David W

AU - Caldwell, Ruth B

AU - Caldwell, Robert William

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AB - Arginase can cause vascular dysfunction by competing with nitric oxide synthase for L-argi-nine 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 +/+AII -/-) or in combination with partial deletion of AI (AI +/+AII -/-). EC-dependent vasorelaxation of aortic rings and arterial fibrosis and stiffness were assessed in relation to arginase activity and expression. Diabetes reduced mean EC-dependent vasorelaxation markedly in diabetic WT and AI +/+AII -/- aortas (53% and 44% vs. controls, respectively) compared with a 27% decrease in AI +/+AII -/- vessels. Coronary fibrosis was also increased in diabetic WT and AI +/+AII -/- mice (1.9- and 1.7-fold vs. controls, respectively) but was not altered in AI +/+AII -/- diabetic mice. Carotid stiffness was increased by 142% in WT diabetic mice compared with 51% in AI +/+AII -/- mice and 19% in AI +/+AII -/- mice. In diabetic WT and AI +/+AII -/- mice, aortic arginase activity and AI expression were significantly increased compared with control mice, but neither parameter was altered in AI +/~AII -/- mice. In summary, AI +/~AII -/- mice exhibit better EC-dependent vasodilation and less vascular stiffness and coronary fibrosis compared with diabetic WT and AI +/+AII -/- mice. These data indicate a major involvement of AI in diabetes-induced vascular dysfunction.

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