Researchers at Vanderbilt University Medical Center have confirmed the existence of an alternative pathway to atherosclerosis, a finding that may lead to new ways to prevent and treat cardiovascular disease.
Atherosclerosis is an inflammatory process that causes the buildup of plaque, deposits of fatty substances including low-density lipoprotein (LDL) cholesterol, in the inner lining of arteries. This results in arterial thickening or hardening, which can restrict blood flow to organs and tissues.
Statin drugs can lower blood levels of LDL cholesterol. However, a significant number of patients on statins with clinically normal or low cholesterol levels remain at risk for cardiovascular disease. This may be because LDL is enriched with microbial small RNAs (msRNAs) that drive pro-inflammatory, atherosclerotic processes, the research suggests.
The study was led by Kasey Vickers, PhD, associate professor of Medicine and Molecular Physiology & Biophysics at Vanderbilt, and former postdoctoral fellow Ryan Allen, PhD, now on the faculty at the University of Arkansas for Medical Sciences in Little Rock.
The researchers found that msRNAs on LDL particles drive the polarization of pro-inflammatory macrophages, a type of white blood cell, and the secretion of inflammatory signaling proteins called cytokines via the activation of the RNA sensor toll-like receptor 8 (TLR8) in macrophages.
Derived from bacteria and fungi from the environment and microbiome, msRNAs normally are cleared from the body by LDLs, Vickers said. However, when LDL levels are abnormally high, the msRNA is deposited in plaque, where it can trigger an inflammatory response that promotes atherosclerosis.
The researchers found that when TLR8 was blocked or when the msRNA cargo was removed from LDL particles, inflammatory activation did not occur and, in mouse models of atherosclerosis, the disease burden was reduced.
These results, published recently in Nature Cell Biology, identify LDL-msRNA as instigators of atherosclerosis-associated inflammation, and suggest that blocking this stimulus may be a new treatment strategy for cardiovascular as well as other inflammatory and metabolic diseases.
The research was supported by grants from the American Heart Association and W.M. Keck Foundation.
Co-authors included Danielle Michell, PhD, Ashley Cavnar, Wanying Zhu, Neil Makhijani, MD, Danielle Contreras, Chase Raby, Elizabeth Semler, Carlisle DeJulius, Mark Castleberry, PhD, Youmin Zhang, Marisol Ramirez-Solano, Shilin Zhao, PhD, Craig Duvall, PhD, Amanda Doran, MD, PhD, Quanhu Sheng, PhD, and MacRae Linton, MD.
