Diabetes-induced vascular dysfunction involves arginase

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

Research output: Contribution to journalArticle

59 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)
Pages (from-to)H159-H166
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, Maritza J.; Iddings, Jennifer A.; Platt, Daniel H.; Irfan Ali, M.; Cederbaum, Stephen D.; Stepp, David W.; Caldwell, Ruth B.; Caldwell, Robert W.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 302, No. 1, 01.01.2012, p. H159-H166.

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 - Iddings, Jennifer A.

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AU - Stepp, David W.

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AU - Caldwell, Robert W.

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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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