Discovery of Atherosclerosis as “Alzheimer’s disease” of Blood Vessels
As we age and our bodies are continuously exposed to damaging agents such as high cholesterol and high blood pressure, the inner walls of the arteries begin to accumulate lipids and immune cells. These atherosclerotic plaques not only impinge on normal blood flow in affected arteries but can become unstable and rupture, leading to a “heart attack”. A major reason for plaque progression and instability is the progressive accumulation of a certain type of immune cell called the macrophage. Macrophages initially gain access to vessel walls having sensed damage to the lining with the intention of rectifying the damage. However, the environment macrophages access is replete with various deleterious lipids and toxins directly leading to macrophage dysfunction. “The macrophage is like a firefighter going into a burning building,” said senior author Babak Razani, MD, PhD, Assistant Professor of Medicine and a member of the Center for Cardiovascular Research. “But in this case, the firefighter is overcome by the conditions. So another firefighter goes in to save the first and is likewise overcome. And another goes in, and the process continues to build on itself and worsen.”
Much research has been devoted to understanding the primary processes that affect the macrophage’s ability to handle the excess lipids and toxins in the plaque. In their study, Razani and colleagues report that one of the important and previously unrecognized processes is the accumulation of protein aggregates in macrophages. They show in both animal models and human vasculature that infiltrating macrophages progressively develop large proteinaceous inclusion bodies very reminiscent of several disorders of the brain such as Alzheimer’s and Parkinson’s disease. This aggregate buildup is largely due to an inability of macrophages to deliver such waste to cellular incinerators called lysosomes. The research team goes on to show that an important component of these aggregates together is a protein called p62. “Macrophages use p62 both as a glue to corral this waste as well as a tag to deliver the waste to the lysosomes for incineration…if p62 is missing, the proteins don’t aggregate,” Razani said. “It’s tempting to think this might be good for the cell, but we showed this is actually worse. It causes more damage than if the waste were corralled into a large “trash bin.”
The study by Razani and colleagues demonstrates that protein aggregate buildup is not only a characteristic feature of atherosclerosis, but it is likely a compensatory response by macrophages to corral the waste in an attempt to minimize further damage. This fundamental observation suggests that future therapeutics in atherosclerosis (and for that matter any disease afflicted by a buildup of waste and aggregates) should focus on fixing the macrophage’s waste disposal system and not on the formation of the aggregates.
This study was published in the January 5th issue of Science Signaling.
Washington People: Angela L. Brown
Angela L. Brown, MD, grew up on her family’s farm in southern Arkansas. At the farm’s peak, the family and its crew cultivated 1,500 acres of cotton, rice and soybeans and managed more than 120 head of cattle. Watching her grandparents persevere through the demands of farm life, and her parents balance their careers — her mother was a high school business teacher, and her father worked in construction — Brown learned the values of hard work and an “anything is possible” mindset.
The farm operation began in the 1920s, when her maternal grandfather inherited 20 acres of farmland. Growing up on the farm, and because Brown and her mother were both only children, Brown’s maternal grandparents played a large role in shaping the person she has become.
Dr. Jeanne Nerbonne named as new Director of the Center for Cardiovascular Research
Jeanne M. Nerbonne, PhD, the Alumni Endowed Professor of Molecular Biology and Pharmacology, has been named director of the Center for Cardiovascular Research.
The Center for Cardiovascular Research within the School of Medicine’s Cardiovascular Division is focused on investigating the biological processes that lead to heart and vascular disease. Nerbonne is the third director of the Center for Cardiovascular Research, which was founded in 1996 by Daniel P. Kelly, MD, former chief of the Cardiovascular Division.