Angiotensin II-induced arterial thickening, fibrosis and stiffening involves elevated arginase function

Anil Bhatta, Lin Yao, Haroldo Alfredo Flores Toque, Alia Shatanawi, Zhimin Xu, Ruth B Caldwell, Robert William Caldwell

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Background: Arterial stiffness (AS) is an independent risk factor for cardiovascular morbidity/mortality. Smooth muscle cell (SMC) proliferation and increased collagen synthesis are key features in development of AS. Arginase (ARG), an enzyme implicated in many cardiovascular diseases, can compete with nitric oxide (NO) synthase for their common substrate, L-arginine. Increased arginase can also provide ornithine for synthesis of polyamines via ornithine decarboxylase (ODC) and proline/collagen via ornithine aminotransferase (OAT), leading to vascular cell proliferation and collagen formation, respectively.We hypothesized that elevated arginase activity is involved in Ang II-induced arterial thickening, fibrosis, and stiffness and that limiting its activity can prevent these changes. Methods and Results: We tested this by studies in mice lacking one copy of the ARG1 gene that were treated with angiotensin II (Ang II, 4 weeks). Studies were also performed in rat aortic Ang II-treated SMC. InWT mice treated with Ang II, we observed aortic stiffening (pulse wave velocity) and aortic and coronary fibrosis and thickening that were associated with increases in ARG1 and ODC expression/activity, proliferating cell nuclear antigen, hydroxyproline levels, and collagen 1 protein expression. ARG1 deletion prevented each of these alterations. Furthermore, exposure of SMC to Ang II (1 μM, 48 hrs) increased ARG1 expression, ARG activity, ODC mRNA and activity, cell proliferation, collagen 1 protein expression and hydroxyproline content. Treatment with ABH prevented these changes. Conclusion: Arginase 1 is crucially involved in Ang II-induced SMC proliferation and arterial fibrosis and stiffness and represents a promising therapeutic target.

Original languageEnglish (US)
Article numbere0121727
JournalPloS one
Volume10
Issue number3
DOIs
StatePublished - Mar 25 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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