Keywords matrix metalloproteinase; insulin resistance; hypertension; endothelial dysfunction; fructose; heat shock protein 90 ---------------------------------------------------------------- Received BACKGROUND AND PURPOSEInsulin 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). EXPERIMENTAL APPROACHWe tested our hypothesis in bovine coronary artery endothelial cells and fructose-fed hypertensive rats (FHR), a model of acquired systolic hypertension and insulin resistance. KEY RESULTSTreatment 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 AND IMPLICATIONSOur 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. AbbreviationsPKB, protein kinase B; Ang II, angiotensin II; APMA, p-aminophenyl mercuric acetate; BCAE cells, bovine coronary artery endothelial cells; Con A, concanavalin A; EGFR, epidermal growth factor receptor; EGM, endothelial growth medium; FHR, fructose hypertensive rat HSP90, heat shock protein 90; ISI, insulin sensitivity index; L-NAME, N G -nitro-L-arginine methyl ester; PE, phenylephrine; SMA, superior mesenteric artery; TIMP, tissue inhibitor of MMP BJP British Journal of Pharmacology