About half of Americans between 45 and 84 have atherosclerosis without knowing it. Diseases linked to atherosclerosis are the leading cause of death in the United States. The condition develops when fats, cholesterol and other substances form plaque in the arteries. As plaque builds, arteries narrow and block blood flow, or can burst, which may lead to blood clotting. The initiation and progression of atherosclerosis are largely driven by genetic and environmental risk factors, but in between, how epigenetic regulation contributes to this pathogenesis remains largely unknown.
Ming He, M.D., Ph.D., an assistant professor in the Division of Molecular and Cellular Pathology, is leading two recently funded studies to investigate the pathobiology of atherosclerosis and explore ways to prevent it before it causes damage.
He received funding from the National Institutes of Health’s National Heart, Lung, and Blood Institute for his first project, titled, “Unveiling the Atheroprone Role of Novel Mechanosensitive Histone Modification.” The five year, $2.7 million R01 will run through May 2030.
“Atherosclerotic plaques typically occur at vascular branches and curvatures, suggesting that disturbed blood flow–induced endothelial dysfunction may initiate atherosclerosis. We recently identified a novel modification on histone H3 that increases in endothelial cells under disturbed blood flow, causing abnormal cell function. This finding may explain how environmental cues-induced epigenetic changes that contribute to this pathological process,” He said.
A histone is a protein that provides structural support for a chromosome, playing an important part in keeping the genome organized within a cell. Modifications of histones alter chromatin structure and gene expression without changing the DNA sequence, a process known as epigenetic regulation. Endothelial cells line the interior of blood vessels and regulate exchanges between the bloodstream and surrounding tissues. The endothelium responds dynamically to shear stress from blood flow. Atheroprone shear stress induces expression of genes that causes endothelial cell dysfunction and plaque formation.
“This research will help us understand how blood vessel cells malfunction, how atherosclerosis is initiated, and how epigenetic mechanisms operate in endothelial cells, while also challenging current patterns of histone modifications in health and disease,” He said.
He also received funding from the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases for his project titled, “Histone H3 O-GlcNAcylation in Endothelial Cells Promotes Diabetic Vascular Complications.” The four year, $2.3 million R01 will run through August 2029.
“About 15 years ago, scientists discovered that if father mice ate a high-fat diet before their daughters were born, the daughters were more likely to develop diabetes. Their DNA did not change, suggesting that epigenetic modifications are involved. Although it is still unclear how these changes are transmitted through the germline, histone modifications can create an epigenetic memory that influences cell function and disease progression,” He said.
He and his team found that high blood sugar can alter histone structure and create an epigenetic memory, making certain culprit genes more easily activated when a 'second hit,' such as increased fatty food intake, occurs, ultimately accelerating atherosclerosis. This environment-induced epigenetic memory may help explain the interaction between environmental and genetic components and shed light on the link between metabolic disorders and cardiovascular disease.
“They are serious research projects, the first study focuses on epigenetic regulation in the initiation of atherosclerosis, while the second project examines epigenetic memory in disease progression. We hope our work will advance understanding of this novel epigenetic regulation in atherosclerosis and ultimately improve human health," He said.