Atherosclerosis

Heart disease kills 600,000 Americans annually, making it the number of cause of death in the U.S.

Overview

The underlying cause of many heart attacks is atherosclerosis, defined as build-up of deposits, or plaques, of cholesterol, calcium, and other substances in arteries. Over time, plaques limit blood flow, and, if they obstruct a vessel like the coronary artery, can trigger a heart attack. Artery blockage in other organs is also hazardous and can damage kidney, the extremities (in the case of peripheral artery disease), or the brain. Plaque rupture also increases the chance of stroke or blood clots in the brain.

Most people are well- schooled in the knowledge that excess cholesterol is a major factor in creation of artery-clogging plaques. But recently investigators have realized that it is actually the inflammation emerging at sites of vessel tissue damage that encourages arterial plaque buildup in the first place, suggesting that dialing down inflammation might be as effective against arterial plaques as dietary or pharmaceutical interventions.

With that knowledge, LJI’s Klaus Ley, M.D., is working on vaccines that target inflammatory factors as a means to reduce atherosclerotic plaque formation. Using a mouse model of atherosclerosis, Ley inoculated animals with the vaccine and observed approximately 50% less plaque in their arteries compared to arteries from unvaccinated mice. Working in collaboration with LJI Alessandro Sette, he has now identified several peptides suitable for vaccinating humans and will test those in mice engineered to harbor a humanized immune system. Their current goal is to enter phase I clinical trials in 2 years. If successful, this achievement would constitute the worlds’ first vaccine for heart disease.

Atherosclerosis and Diabetes
Atherosclerosis and diabetes go hand in hand: type 1 and type 2 diabetes sufferers are four times more likely to die of heart attack than the general population. To understand why, LJI’s Catherine Hedrick, Ph.D., studies how elevated cholesterol contributes to atherosclerosis. To that end, she genetically engineered mice to lack a protein that transports cholesterol out of cells in order to analyze experimentally what happens when immune cells remain abnormally packed with cholesterol. She observed that the repertoire of immune cell subtypes differed between normal and engineered mice, and furthermore, that T cells of engineered mice fed a “western” (fatty) diet produced inordinately high levels of pro-inflammatory cytokines. This hints that cholesterol overload may prompt cells to overproduce inflammatory factors that foment plaque formation.

A fascinating corollary to this story has recently emerged. Hedrick observed when infused with tumor cells, the very same mice lacking the cholesterol transporter exhibited lower rates of bladder cancer and melanoma than did normal animals. Furthermore, their bloodstream showed an upsurge in the number of macrophages, immune cells capable of scavenging and thus carting off tumor cells. This finding suggests that high cellular cholesterol content could push immune cells like macrophages into tumor-fighting mode and presents a very intriguing paradox: namely that inflammation that is deadly in the context of atherosclerosis may be beneficial when it comes to cancer.

FACULTY MEMBERS

Catherine “Lynn” Hedrick, Ph.D.
Klaus Ley, M.D.

From The Lab

Apr 12, 2018 // Circulation

LJI researchers are one step closer to an effective anti-atherosclerosis vaccine

Mar 15, 2018 // Nature Communications

Western diet depletes artery-protecting immune cells

Nov 1, 2016

LJI scientists flip molecular switches to distinguish closely related immune cell populations

Aug 1, 2016 // WebMD

The future of vaccines

Jul 20, 2016 // San Diego Union Tribune

Antibodies could stop heart disease, study finds