title: Inhibition of matrix metalloproteinase-2 improves endothelial function and prevents hypertension in insulin-resistant rats.
abstract: OBJECTIVE
  Insulin resistance is often found to be associated with high blood pressure. We propose that in insulin-resistant hypertension, endothelial dysfunction is the consequence of increased activity of vascular MMP-2. As MMP-2 proteolytically cleaves a number of extracellular matrix proteins, we hypothesized that MMP-2 impairs endothelial function by proteolytic degradation of endothelial NOS (eNOS) or its cofactor, heat shock protein 90 (HSP90).
  
  
  METHODS
  We tested our hypothesis in bovine coronary artery endothelial cells and fructose-fed hypertensive rats (FHR), a model of acquired systolic hypertension and insulin resistance.
  
  
  RESULTS
  Treatment of FHRs with the MMP inhibitor doxycycline, preserved endothelial function as well as prevented the development of hypertension, suggesting that MMPs impair endothelial function. Furthermore, incubating endothelial cells in vitro with a recombinant MMP-2 decreased NO production in a dose-dependent manner. Using substrate cleavage assays and immunofluorescence microscopy studies, we found that MMP-2 not only cleaves and degrades HSP90, an eNOS cofactor but also co-localizes with both eNOS and HSP90 in endothelial cells, suggesting that MMPs functionally interact with the eNOS system. Treatment of FHRs with doxycycline attenuated the decrease in eNOS and HSP90 expression but did not improve insulin sensitivity.
  
  
  CONCLUSIONS
  Our data suggest that increased activity of MMP-2 in FHRs impairs endothelial function and promotes hypertension. Inhibition of MMP-2 could be a potential therapeutic strategy for the management of hypertension.
authors: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
authors: P R
authors: PR
authors: Nagareddy
authors: P S
authors: PS
authors: Rajput
authors: H
authors: H
authors: Vasudevan
authors: B
authors: B
authors: McClure
authors: U
authors: U
authors: Kumar
authors: K M
authors: KM
authors: Macleod
authors: J H
authors: JH
authors: McNeill
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002417:Cattle; D002478:Cells, Cultured; D004318:Doxycycline / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005632:Fructose; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D061965:Matrix Metalloproteinase Inhibitors; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018841:HSP90 Heat-Shock Proteins; D061965:Matrix Metalloproteinase Inhibitors; D005632:Fructose; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D004318:Doxycycline