Gary Owens of the Robert M. Berne Cardiovascular Research Center (CVRC) Awarded 3.2 Million R01 Grant

Role of IL-6 trans signaling in atherosclerosis development and late-stage pathogenesis

Gary Owens, PhD
Professor of Molecular Physiology and Biological Physics

Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions are the underlying cause of most heart attacks or stroke and are the leading cause of death in the United States and worldwide. Whereas there is general agreement that atherosclerosis is a chronic inflammatory disease, multiple large clinical trials of drugs that globally inhibit inflammation have failed to get FDA approval due to them having modest or no beneficial effects on the incidence of a fatal or non-fatal heart attack or stroke, and an increase in lethal infection because patients are immuno-compromised.

We postulate that a major reason for the failure of global anti-inflammatory agents is because they inhibit not only detrimental chronic pro-inflammatory responses that exacerbate atherosclerosis, but also evolutionarily conserved beneficial acute inflammatory processes necessary for resistance to infection, resolution of inflammation, and tissue injury-repair processes important for enhancing the stability of atherosclerotic lesions and reducing the chance of rupture or erosion. Studies in this proposal will use novel mouse models and analysis methods to determine if selective inhibition of interleukin-6 (IL-6) trans signaling, which is believed to be a key mediator of the transition from acute (beneficial) to chronic (detrimental) inflammation, promotes formation of more stable atherosclerotic lesions and a reduced probability of lesion rupture or erosion but without impaired immuno-competence. If so, results would be of major significance in that they would suggest that human clinical trials should focus on testing selective IL-6 trans inhibitors not global inhibitors of IL-6 responses as is currently the case with a recently initiated large Phase 3 clinical trial.