Inhibition of matrix metalloproteinase‐2 improves endothelial function and prevents hypertension in insulin‐resistant rats

Abstract

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

Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion

“…Inhibition of MMPs reduces the over-expression of contractile proteins (myosin light chain kinase and myosin light chain II) and their transcriptional activators in insulin resistant vascular smooth muscle cells [64]. In a model of hypertension produced by high fructose diet fed rats, MMP-2 produces endothelial dysfunction and acquired systolic hypertension with insulin resistance that is inhibited by MMP blockade [65]. …”

“…A functional role for MMP-2 was described and mice that are lacking this enzyme gain less weight after high fat diet compared to wild type controls [77]. Moreover, inhibition of this protease in an insulin resistance model was shown to improve endothelial dysfunction and prevent hypertension [65]. …”

Gelatinases and their tissue inhibitors in a group of subjects with obstructive sleep apnea syndrome

“…However, MMP-2 seems to be associated with a more stable plaque phenotype and rare haemorrhages [11]. MMPs activity is also regulated by the four tissue inhibitors of MMP (TIMPs): TIMP-1 inhibits especially MMP-9 while TIMP-2 inhibits especially MMP-2 [23]. An altered expression of MMPs and TIMPs has been observed in OSAS.…”

Insights into the Activity, Differential Expression, Mutual Regulation, and Functions of Matrix Metalloproteinases and A Disintegrin and Metalloproteinases in Hypertension and Cardiac Disease

“…Among the tetracycline class of drugs, doxycycline demonstrates the greatest inhibition of MMPs and is approved for use as an MMP inhibitor in the treatment of periodontitis [138]. Doxycycline has shown beneficial effects in treating diseases including aortic aneurysm and Marfan’s syndrome, intracranial aneurysm, and hypertension in renovascular rats, spontaneously hypertensive rats, and fructose-fed rats [25,64,139,140,141,142]. However, treatment of stroke-prone spontaneously hypertensive rats with doxycycline over a period of either 6 or 26 weeks does not ameliorate hypertension or cardiac hypertrophy and exacerbates cardiac fibrosis [143,144].…”