Journal article
Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion
Cardiovascular research, Vol.84(1), pp.137-144
10/01/2009
DOI: 10.1093/cvr/cvp176
PMCID: PMC2741344
PMID: 19482949
Abstract
Aims: Oxidative stress accompanies inflammatory and vascular diseases. The objective of this study was to explore whether reactive oxygen species can activate shedding of platelet receptors and thus suppress platelet function.
Methods and results: Hydrogen peroxide and glucose oxidase were chosen to model oxidative stress in vitro. We demonstrate that oxidative damage activated tumour necrosis factor-alpha-converting enzyme (TACE) and induced shedding of its targets, glycoprotein (GP) Ibalpha and GPV, in murine and human platelets. Also, 12-HpETE, a peroxide synthesized in the platelet lipoxygenase pathway, induced TACE-mediated receptor cleavage. The TACE activation was independent of platelet activation, as alpha-granule secretion, activation of alphaIIbbeta3, or phosphatidylserine expression was not observed. TACE activation induced by hydrogen peroxide was dependent on p38 mitogen-activated protein kinase signalling, whereas protein kinase C, phosphoinositide 3-kinase, and caspases were not involved. Inhibition of p38 cytoplasmic targets, phospholipase A(2) and heat shock protein 27, did not prevent shedding, whereas blocking 12-lipoxygenase or Src kinase slightly inhibited TACE activation. The loss of the GPIbalpha receptor induced by oxidative stress rendered platelets unable to incorporate into a growing thrombus in vivo.
Conclusion: Oxidative stress can render platelets functionally less active by shedding key adhesion receptors via the activation of p38. This suggests that oxidative injury of platelets may attenuate their function.
Details
- Title: Subtitle
- Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion
- Creators
- Alexander Brill - Immune Disease InstituteAnil K Chauhan - Immune Disease InstituteMatthias Canault - Immune Disease InstituteMeghan T Walsh - Immune Disease InstituteWolfgang Bergmeier - Thomas Jefferson UniversityDenisa D Wagner - Immune Disease Institute
- Resource Type
- Journal article
- Publication Details
- Cardiovascular research, Vol.84(1), pp.137-144
- Publisher
- Oxford University Press
- DOI
- 10.1093/cvr/cvp176
- PMID
- 19482949
- PMCID
- PMC2741344
- ISSN
- 0008-6363
- eISSN
- 1755-3245
- Language
- English
- Date published
- 10/01/2009
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094481402771
Metrics
12 Record Views