Matrix metalloproteinase-2-induced epidermal growth factor receptor transactivation impairs redox balance in vascular smooth muscle cells and facilitates vascular contraction

Redox Biology
Alejandro F PradoRaquel F Gerlach

Abstract

Increased reactive oxygen species (ROS) formation may enhance matrix metalloproteinase (MMP)-2 activity and promote cardiovascular dysfunction. We show for the first time that MMP-2 is upstream of increased ROS formation and activates signaling mechanisms impairing redox balance. Incubation of vascular smooth muscle cells (VSMC) with recombinant MMP-2 increased ROS formation assessed with dihydroethidium (DHE) by flow cytometry. This effect was blocked by the antioxidant apocynin or by polyethylene glycol-catalase (PEG-catalase), and by MMP inhibitors (doxycycline or GM6001). Next, we showed in HEK293 cells that MMP-2 transactivates heparin-binding epidermal growth factor (HB-EGF) leading to EGF receptor (EGFR) activation and increased ROS concentrations. This effect was prevented by the EGFR kinase inhibitor Ag1478, and by phospholipase C (PLC) or protein kinase C (PKC) inhibitors (A778 or chelerythrine, respectively), confirming the involvement of EGFR pathway in MMP-2-induce responses. Next, we showed that intraluminal exposure of aortas to MMP-2 increased vascular MMP-2 levels detected by immunofluorescence and gelatinolytic activity (by in situ zimography) in association with increased ROS formation. This effect was inhibi...Continue Reading

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Citations

Dec 21, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kehong ChenYani He
Jun 25, 2020·American Journal of Physiology. Cell Physiology·Zihan MaWei Kong
Aug 15, 2019·Experimental and Therapeutic Medicine·Zongxiang ChenJuan Du
Jan 9, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Rita MattaAnjelica L Gonzalez
Jul 26, 2021·Cellular Signalling·Srikanth PalanisamyKathleen Gabrielson
May 11, 2020·Current Hypertension Reviews·Alejandro F do PradoCésar A Meschiari

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Datasets Mentioned

BETA
GM6001

Methods Mentioned

BETA
zymography
flow cytometry
PMA

Software Mentioned

Protowin
Graph Pad
ImageJ
Graph Pad Prism

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