Faculty Collaboration Database

Platelet CD36 promotes thrombosis by activating redox sensor ERK5 in hyperlipidemic conditions. Blood 2017 May 25;129(21):2917-2927

Date

03/25/2017

Pubmed ID

28336528

Pubmed Central ID

PMC5445574

DOI

10.1182/blood-2016-11-750133

Scopus ID

2-s2.0-85019661296 (requires institutional sign-in at Scopus site)   72 Citations

Abstract

Atherothrombosis is a process mediated by dysregulated platelet activation that can cause life-threatening complications and is the leading cause of death by cardiovascular disease. Platelet reactivity in hyperlipidemic conditions is enhanced when platelet scavenger receptor CD36 recognizes oxidized lipids in oxidized low-density lipoprotein (oxLDL) particles, a process that induces an overt prothrombotic phenotype. The mechanisms by which CD36 promotes platelet activation and thrombosis remain incompletely defined. In this study, we identify a mechanism for CD36 to promote thrombosis by increasing activation of MAPK extracellular signal-regulated kinase 5 (ERK5), a protein kinase known to be exquisitely sensitive to redox stress, through a signaling pathway requiring Src kinases, NADPH oxidase, superoxide radical anion, and hydrogen peroxide. Pharmacologic inhibitors of ERK5 blunted platelet activation and aggregation in response to oxLDL and targeted genetic deletion of ERK5 in murine platelets prevented oxLDL-induced platelet deposition on immobilized collagen in response to arterial shear. Importantly, in vivo thrombosis experiments after bone marrow transplantation from platelet-specific ERK5 null mice into hyperlipidemic apolipoprotein E null mice showed decreased platelet accumulation and increased thrombosis times compared with mice transplanted with ERK5 expressing control bone marrows. These findings suggest that atherogenic conditions critically regulate platelet CD36 signaling by increasing superoxide radical anion and hydrogen peroxide through a mechanism that promotes activation of MAPK ERK5.

Author List

Yang M, Cooley BC, Li W, Chen Y, Vasquez-Vivar J, Scoggins NO, Cameron SJ, Morrell CN, Silverstein RL

Authors

Yiliang Chen PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Roy L. Silverstein MD Professor in the Medicine department at Medical College of Wisconsin
Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Allografts
Animals
Apolipoproteins E
Blood Platelets
Bone Marrow Transplantation
CD36 Antigens
Humans
Hyperlipidemias
Lipoproteins, LDL
MAP Kinase Signaling System
Mice
Mice, Mutant Strains
Mitogen-Activated Protein Kinase 7
NADPH Oxidases
Platelet Activation
Thrombosis