Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 29, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp176
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion
1 Immune Disease Institute, Boston, MA 02115, USA
2 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
3 Deptartment of Medicine and Cardeza Foundation, Thomas Jefferson University, Philadelphia, PA 19107, USA
Correspondence: Denisa D. Wagner, Immune Disease Institute, 3 Blackfan Circle, 3rd floor, Boston, MA 02115, phone: 617-713-8300; fax: 617-713-8333; e-mail: wagner{at}idi.harvard.edu
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 tumor necrosis factor-alpha-converting enzyme (TACE) and induced shedding of its targets, glycoprotein (GP) Ib
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 -granule secretion, activation of IIbβ3 or phosphatidylserine expression were not observed. TACE activation induced by hydrogen peroxide was dependent on p38 mitogen-activated protein kinase signaling whereas protein kinase C, phosphoinositide 3-kinase, and caspases were not involved. Inhibition of p38 cytoplasmic targets, phospholipase A2 and heat shock protein 27 did not prevent shedding, whereas blocking 12-lipoxygenase or Src kinase slightly inhibited TACE activation. The loss of the GPIb 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 activation of p38. This suggests that oxidative injury of platelets may attenuate their function.
Time for primary review: 17 Days
* Current address: Dept of Internal Medicine, Division of Hematology/Oncology, 3188 Med Labs, Iowa City, IA, USA