title: Angiotensin II-induced arterial thickening, fibrosis and stiffening involves elevated arginase function.
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.
  
  
  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. In WT 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.
  
  
  CONCLUSIONS
  Arginase 1 is crucially involved in Ang II-induced SMC proliferation and arterial fibrosis and stiffness and represents a promising therapeutic target.
authors: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia, United States of America.
authors: Anil
authors: A
authors: Bhatta
authors: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia, United States of America.
authors: Lin
authors: L
authors: Yao
authors: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia, United States of America.
authors: Haroldo A
authors: HA
authors: Toque
authors: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia, United States of America.
authors: Alia
authors: A
authors: Shatanawi
authors: Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors: Zhimin
authors: Z
authors: Xu
authors: Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America; Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
authors: Ruth B
authors: RB
authors: Caldwell
authors: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia, United States of America.
authors: R William
authors: RW
authors: Caldwell
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005355:Fibrosis / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D063177:Pulse Wave Analysis; D051381:Rats; D059289:Vascular Stiffness / Q000187:drug effects*
chemical_list: D000804:Angiotensin II; D001119:Arginase