A new study published in the Journal of Clinical Investigation Insight has identified a unique autoantibody directed against a cellular protein named GRP78 which accelerates atherosclerosis, the underlying cause of cardiovascular disease.

The research team, led by McMaster University vascular biologist Richard Austin, has now demonstrated that anti-GRP78 autoantibodies can bind to GRP78 on the surface of lesion-resident endothelial cells and speed up atherosclerosis.

The study also demonstrated that mouse models of atherosclerosis as well as patients with established cardiovascular disease have significantly elevated blood levels of these autoantibodies that both correlate and contribute to disease progression.

“Normally, GRP78 is embedded in cells where it acts as a molecular chaperone to assist in protein folding. However, we made the surprising discovery that GRP78 moves to the surface of lesion-resident endothelial cells and activates the immune system to generate anti-GRP78 autoantibodies,” said Richard Austin, the senior author of the publication and professor in the Department of Medicine at McMaster.

“This increase in the levels of anti-GRP78 autoantibodies have the unique ability to bind to GRP78 on the surface of endothelial cells which drives several critical stages of atherosclerosis,” added Ali Al-Hashimi, co-first author of the publication and postdoctoral fellow with Austin.

“This is what accelerates atherogenesis and hence the increase in cardiovascular disease.”

The research was a collaborative effort with Wadih Arap and Renata Pasqualini from the Rutgers Cancer Institute of New Jersey and Katey Rayner from the University of Ottawa. The Austin research laboratory is located at the Hamilton Centre for Kidney Research which is part of the Research Institute of St. Joseph’s Healthcare Hamilton.

"In recent work, our groups showed that autoantibodies against GRP78 stimulated tumor growth,” said Pasqualini, who is chief of the Division of Cancer Biology at Rutgers New Jersey Medical School and a Rutgers Cancer Institute of New Jersey member.

“Here, this collaborative research adds up to yet another level of complexity to the biology of stress-response chaperones and their corresponding autoimmune humoral response by demonstrating a role in atherosclerosis with potential importance to the management of cardiovascular disease patients."

“The observation that the FDA-approved and commercially available drug enoxaparin (Lovenox) may protect against atherosclerotic lesion growth and may stabilize the plaque by specifically disrupting the binding of anti-GRP78 autoantibodies to cell surface-associated GRP78 is mechanistically interesting and could well open up new therapeutic strategies,” added Dr. Arap, who is director of Rutgers Cancer Institute of New Jersey in Newark and chief of the Division of Hematology/Oncology at Rutgers New Jersey Medical School.

“Given these exciting findings, we are now in the process of identifying novel compounds or biologics having the capability of specifically inhibiting this association as a means of reducing the risk of cardiovascular disease,” said Al-Hashimi.