# ERK5 and CD36 link oxidative stress to platelet dysfunction and ischemic injury

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $632,045

## Abstract

Risk of arterial thrombosis, including myocardial infarction (MI) and stroke, is increased in the setting of systemic
disease states associated with chronic inflammation, including cancer, diabetes, atherosclerosis and obesity.
Inappropriate platelet activation is a driving mechanism of thrombosis in these settings and recent studies
suggest that mechanisms of platelet activation in diseased states may be different from those in normal healthy
conditions. Dissecting these novel mechanisms is the central goal of this multi-PI proposal. Recent published
and preliminary studies showed that endogenous danger signals well known to be generated during diseased
states, including oxidized low density lipoprotein, advanced glycated proteins, cell-derived microparticles, and
S100A peptides all interact with a specific platelet receptor, CD36, to initiate intracellular signals that promote
platelet activation and thrombosis. Furthemore platelets were found to express the MAP kinase ERK5, a known
sensor of reactive oxygen species (ROS). Platelet ERK5 was then shown to act as a redox switch responsive to
extracellular ROS under ischemic conditions, promoting platelet activation and enhancing myocardial damage
during MI; and ERK5 was found to be activated downstream of CD36 in response to oxLDL-mediated ROS
generation. Platelet specific deletion of ERK5 ameliorated platelet activation and the pro-thrombotic state
associated with hyperlipidemic oxidant stress. We thus hypothesize that ERK5 serves as a central “node” in
pathologic platelet activation, responding to receptor-mediated intracellular signals triggered by CD36 and non-
receptor mediated extracellular signals (ROS) mediated by tissue ischemia, through both its signaling and protein
regulation activities. Specific aim 1 will test the hypothesis that specific ROS generated by CD36 signaling
maintains platelets in a pro-activated state via activation of ERK5. Human In vitro and mouse in vivo studies will
use genetic models, diet-induced disease models, and highly specific CD36 ligands to identify critical cell
membrane partners necessary for CD36-mediated ERK5 activation, as well as downstream effectors of ROS
and ERK5 in platelets; and to determine how ERK5 signaling integrates with “classic” pathways of platelet
activation to promote thrombosis. Aim 2 will test the hypothesis that ERK5 regulates platelet protein expression
by modulating platelet protein translation and/or protein ubiquitination. In vitro and in vivo models will be used to
determine whether changes in platelet protein expression in response to ROS are dependent on protein
synthesis, degradation, or both. Aim 3 will determine mechanisms by which platelet ERK5 activation in the setting
of tissue ischemia and extracellular ROS increases tissue and organ dysfunction. Genetic and pharmacologic
approaches and in vivo models of MI and oxidant stress will be used. By understanding mechanisms of platelet
ERK5 activation and downstream pathways t...

## Key facts

- **NIH application ID:** 9841989
- **Project number:** 5R01HL142152-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** CRAIG N MORRELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $632,045
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841989

## Citation

> US National Institutes of Health, RePORTER application 9841989, ERK5 and CD36 link oxidative stress to platelet dysfunction and ischemic injury (5R01HL142152-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9841989. Licensed CC0.

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