title: Bortezomib, a proteasome inhibitor, attenuates angiotensin II-induced hypertension and aortic remodeling in rats.
abstract: BACKGROUND
  Hypertension is a highly prevalent disorder and a major risk factor for cardiovascular diseases. Hypertensive vascular remodeling is the pathological mal-adaption of blood vessels to the hypertensive condition that contributes to further development of high blood pressure and end-organ damage. Hypertensive remodeling involves, at least in part, changes in protein turnover. The ubiquitin proteasome system (UPS) is a major protein quality and quantity control system. This study tested the hypothesis that the proteasome inhibitor, bortezomib, would attenuate AngII-induced hypertension and its sequelae such as aortic remodeling in rats.
  
  
  RESULTS
  Male Sprague Dawley rats were subjected to AngII infusion for two weeks in the absence or presence of bortezomib. Mean arterial pressure was measured in conscious rats. Aortic tissue was collected for estimation of wall area, collagen deposition and expression of tissue inhibitors of matrix metalloproteases (TIMP), Ki67 (a marker of proliferation), reactive oxygen species (ROS) and VCAM-1 (a marker of inflammation). AngII infusion increased arterial pressure significantly (160±4 mmHg vs. vehicle treatment 133±2 mmHg). This hypertensive response was attenuated by bortezomib (138±5 mmHg). AngII hypertension was associated with significant increases in aortic wall to lumen ratio (∼29%), collagen deposition (∼14%) and expression of TIMP1 and TIMP2. AngII also increased MMP2 activity, proteasomal chymotrypsin-like activity, Ki67 staining, ROS generation and VCAM-1 immunoreactivity. Co-treatment of AngII-infused rats with bortezomib attenuated these AngII-induced responses.
  
  
  CONCLUSIONS
  Collectively, these data support the idea that proteasome activity contributes to AngII-induced hypertension and hypertensive aortic vascular remodeling at least in part by modulating TIMP1/2 and MMP2 function. Preliminary observations are consistent with a role for ROS, inflammatory and proliferative mechanisms in this effect. Further understanding of the mechanisms by which the proteasome is involved in hypertension and vascular structural remodeling may reveal novel targets for pharmacological treatment of hypertension, hypertensive remodeling or both.
authors.affiliation: Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, United States of America.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Li
authors.forename: Curtis K
authors.initials: CK
authors.lastname: Kost
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Martin
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology*; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D061988:Proteasome Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; D000069286:Bortezomib