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Angiotensin II‐induced arterial fibrosis and stiffness is prevented in arginase 1‐deficient mice (1065.8)
Author(s) -
Bhatta Anil,
Xu Zhimin,
Caldwell Ruth,
Caldwell R. William
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1065.8
Subject(s) - arginase , ornithine decarboxylase , hydroxyproline , angiotensin ii , endocrinology , ornithine , medicine , fibrosis , chemistry , nitric oxide , arginine , enzyme , biochemistry , amino acid , blood pressure
Arterial stiffness (AS) is an independent risk factor for cardiovascular morbidity and mortality. Increases in smooth muscle cell (SMC) proliferation and collagen synthesis are key features in development of AS. Arginase (ARG), an enzyme implicated in many cardiovascular diseases and fibrosis, can compete with nitric oxide (NO) synthase for their common substrate, L‐arginine. Increased ARG, in addition to reducing NO production, can also elevate levels of ornithine for synthesis of polyamines via ornithine decarboxylase (ODC) and proline/collagen via ornithine aminotransferase (OAT), leading to increases in cell proliferation and collagen formation, respectively. In order to investigate the role of ARG1 in AS, wild type (WT) or ARG1 KO mice were infused with angiotensin II (Ang II, 4 wks). Ang II infusion in WT mice increased levels of aortic ARG activity/expression, ODC mRNA, hydroxyproline, type I collagen, fibrosis, and induced AS (as shown by increased pulse wave velocity). These effects did not occur in Ang II infused ARG1 KO mice. Exposure of rat aortic SMCs to Ang II (1 μM, 48 hrs) increased ARG activity (57%), cell proliferation (22%), type 1 collagen protein (44%), ODC mRNA (25%), and hydroxyproline (22%). Treatment with ARG inhibitor ABH prevented these changes. In summary, ARG1 is crucially involved in arterial SMC proliferation, fibrosis and stiffness and represents a promising therapeutic target.