Coronary artery disease (CAD), more commonly called heart disease, affects 16 million Americans. It’s often caused by a hardening and narrowing of the arterial walls, a process known as atherosclerosis, which prevents oxygen and nutrients from reaching the heart. CAD causes one in five deaths in the U.S.
Treatment efficacy for CAD varies from patient to patient, partly because for years, doctors and researchers have predominantly tried to alleviate atherosclerosis by reducing individuals’ cholesterol levels.
“The catch is that 20-50 percent of patients who come into the emergency room with a heart attack have normal cholesterol,” explained Dr. Ken Fujise, a physician-scientist and director of the Division of Cardiology within the University of Texas Medical Branch, Galveston.
In other words, high cholesterol may not be the cause of many peoples’ heart disease.
Fortunately, there may soon be an alternative treatment method for CAD. Three Boise State University researchers have teamed with Dr. Fujise to develop fortilin inhibitors that can be used to block atherosclerosis. The team has been awarded a four-year, $1 million grant from the National Institutes of Health, $393,064 of which will be used to fund new research at Boise State.
Working on this project at Boise State will be Owen McDougal, a professor and chair of the Department of Chemistry and Biochemistry; Matt King, an assistant professor in the Department of Chemistry and Biochemistry; and Lisa Warner, an assistant research professor in the Biomolecular Research Center.
“This condition is a huge financial burden on society – $286 billion is spent each year to care for people affected by it,” Dr. Fujise said. “Society needs something more potent and a lot cheaper. That’s why our group decided to target fortilin.”
Fortilin is a protein that has multiple functions within the human body – one being that it protects fat cells from programmed cell death. Here’s how it works: macrophages collect cholesterol and lipids from our blood stream, which promotes fat cell enlargement. With fortilin protecting them, these fat cells simply accumulate, expand and multiply until they rupture – in other words, until a person has a heart attack.
“If we attack fortilin, we can prevent fat cells from multiplying and getting bigger,” Dr. Fujise explained. He cited a recent genetic study of mice with sky-high cholesterol, which found that decreasing their concentration of fortilin lowered instances of atherosclerosis. “This study shows that by targeting fortilin, you can protect your arteries from atherosclerosis and heart attack.”
The team’s four-year goal is to create a clinical-grade compound that targets fortilin. They already have prototypes of three molecules identified as potential compound candidates; now their task is to refine their structure.
At Boise State, King will be in charge of evaluating the compounds computationally. “I’ll be looking at the interactions between the small molecule and the fortilin protein, and determining what modifications can be made to these compounds to increase the strength of the interaction,” he said.
Warner will be using biomolecular nuclear magnetic resonance (NMR) to observe where each small molecule is interacting on the protein. “There are binding pockets on the protein, which Matt has identified as potential spots of interaction. We’ll be observing to find exact points for further computational study,” she said.
McDougal will be collaborating with Warner and King on their work, while also training a Boise State graduate student to help conduct the computational cell-based assays protein expression and NMR studies.
“Boise State has the premier NMR facility in the state,” McDougal said. “When we brought it on in 2007, it was intended for this usage. Finally, after a decade, we have the capability to actually do this work.”
“It’s not far off to say our goal is to cure heart disease,” he added.
Research reported in this article was supported by the National Heart, Lung, and Blood Institute of NIH under award number R01HL138992. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.