Chronic inflammation is a major driver of atherosclerotic cardiovascular disease, a leading cause of death and disability.
Now, researchers at Vanderbilt University Medical Center have identified a novel target that could slow the progression of atherosclerosis and heart inflammation: calcium/calmodulin-dependent protein kinase IV (CaMK4), an enzyme involved in modulating the body’s inflammatory and immune responses.
Increased CaMK4 expression has been found in plaque, a buildup of fat, cholesterol and other substances in blood vessels that can reduce blood flow, trigger blood clots and cause heart attacks, strokes and death.
To better understand the role of CaMK4 in plaque formation, the researchers used a hypercholesterolemic (high cholesterol) mouse model to induce atherosclerotic lesions in the heart.
Both mouse and human atherosclerotic lesions are known to be populated by immune cells derived from monocytes, called macrophages. These cells had increased CAMK4 expression, the researchers found.
Genetically altered mice that lacked CaMK4 had fewer numbers of these inflammatory immune cells. In addition, bone marrow-derived macrophages in which the gene for CaMK4 had been deleted displayed more reparative functions, the ability to repair blood vessels damaged by disease, than did control macrophages with normal CaMK4 expression.
These findings, reported May 8 in Arteriosclerosis, Thrombosis and Vascular Biology, a journal of the American Heart Association and American Stroke Association, suggest that regulating the immune response to hypercholesterolemia through CaMK4 could enhance repair and slow disease progression.
Amanda Doran, MD, PhD, assistant professor of Medicine in the Division of Cardiovascular Medicine, is the paper’s corresponding author. The first author is Azuah Gonzalez, a graduate student in the Doran lab.
Other VUMC co-authors are Matthew Dungan, Katherine Gu, Ashley Cavnar, MSc, Danielle Michell, PhD, Lindsay Davidson, PhD, Calliope Cutchins, Yunli Chu. Zachary Kohutek, MD, PhD, MacRae Linton, MD, P. Brent Ferrell, MD, Kasey Vickers, PhD, and Jonathan Brown, MD.
This work was supported by grants from the American Heart Association and National Institutes of Health: 17FTF33660643, R01HL159487, and T32AI138932.
Guillermo Sanchez, PhD, is a staff scientist in the lab of Nick Zachos, PhD, associate professor of Surgery and Cell and Developmental Biology at Vanderbilt.
