Dataset Information

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

ABSTRACT:

Background and purpose

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).

Experimental approach

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.

Key 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 and implications

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.

SUBMITTER: Nagareddy PR

PROVIDER: S-EPMC3315042 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Nagareddy P R PR Rajput P S PS Vasudevan H H McClure B B Kumar U U Macleod K M KM McNeill J H JH

British journal of pharmacology 20120201 3

<h4>Background and purpose</h4>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).<h4>Experimental approach ...[more]

PMID: 21740410

Similar Datasets

Project description:IntroductionThe glymphatic system offers a perivascular pathway for the clearance of pathological proteins and metabolites to optimize neurological functions. Glymphatic dysfunction plays a pathogenic role in Parkinson's disease (PD); however, the molecular mechanism of glymphatic dysfunction in PD remains elusive.ObjectiveTo explore whether matrix metalloproteinase-9 (MMP-9)-mediated β-dystroglycan (β-DG) cleavage is involved in the regulation of aquaporin-4 (AQP4) polarity-mediated glymphatic system in PD.Methods1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and A53T mice were used in this study. The glymphatic function was evaluated using ex vivo imaging. TGN-020, an AQP4 antagonist, was administered to investigate the role of AQP4 in glymphatic dysfunction in PD. GM6001, an MMP-9 antagonist, was administered to investigate the role of the MMP-9/β-DG pathway in regulating AQP4. The expression and distribution of AQP4, MMP-9, and β-DG were assessed using western blotting, immunofluorescence, and co-immunoprecipitation. The ultrastructure of basement membrane (BM)-astrocyte endfeet was detected using transmission electron microscopy. Rotarod and open-field tests were performed to evaluate motor behavior.ResultsPerivascular influx and efflux of cerebral spinal fluid tracers were reduced in MPTP-induced PD mice with impaired AQP4 polarization. AQP4 inhibition aggravated reactive astrogliosis, glymphatic drainage restriction, and dopaminergic neuronal loss in MPTP-induced PD mice. MMP-9 and cleaved β-DG were upregulated in both MPTP-induced PD and A53T mice, with reduced polarized localization of β-DG and AQP4 to astrocyte endfeet. MMP-9 inhibition restored BM-astrocyte endfeet-AQP4 integrity and attenuated MPTP-induced metabolic perturbations and dopaminergic neuronal loss.ConclusionAQP4 depolarization contributes to glymphatic dysfunction and aggravates PD pathologies, and MMP-9-mediated β-DG cleavage regulates glymphatic function through AQP4 polarization in PD, which may provide novel insights into the pathogenesis of PD.

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets