A team of Vanderbilt University Medical Center researchers has received a $1 million grant from the W.M. Keck Foundation to explore a novel model of atherosclerosis development.
The grant is one of five awarded nationally this year for medical research projects “that are high-risk with the potential for transformative impact,” according to the foundation.
The Vanderbilt team has proposed that small microbial RNAs carried on low-density lipoprotein (LDL) particles trigger inflammation and drive atherosclerosis — the narrowing of arteries from the build-up of plaque. As the underlying cause of heart attack and stroke, atherosclerosis is the main culprit in cardiovascular disease, which affects one in three people and is the leading cause of death worldwide.
“For 50 years, we have viewed this major health issue through the lens of cholesterol,” said Kasey Vickers, PhD, assistant professor of Medicine and Molecular Physiology and Biophysics. “We’ve realized that cholesterol is only one side of the story.”
Statin drugs, which inhibit cholesterol synthesis and promote clearance of LDL particles (the ‘bad’ cholesterol), reduce cardiovascular disease events, but not to zero.
“We have good medications to address the cholesterol side of atherosclerosis, but a significant number of patients on statins with clinically normal or low cholesterol levels have what’s called ‘residual risk’ — they are still at risk for cardiovascular events,” said MacRae Linton, MD, director of the Vanderbilt Lipid Clinic and Atherosclerosis Research Unit. Linton is the Dr. Stephen Schillig Jr. and Mary Schillig Professor of Medicine.
Vickers, Linton and team members Quanhu Sheng, PhD, assistant professor of Biostatistics, and Ryan Allen, PhD, research instructor in Medicine, are addressing the “other” side of the atherosclerosis story: vascular inflammation.
There has been growing interest in the idea that “to really cure atherosclerosis, we have to treat the inflammatory component,” Vickers said.
“The recent CANTOS trial was proof-of-principal that targeting inflammation in atherosclerosis will reduce cardiovascular events,” Linton said. “But the drug being tested in that study broadly suppressed the immune response and increased the number of severe infections.”
The VUMC team aims to target the trigger of inflammation in atherosclerosis, rather than the immune response.
During his postdoctoral fellowship at the National Institutes of Health, Vickers discovered that in addition to cholesterol, lipoprotein particles (HDL and LDL) carry small non-coding RNAs (sRNAs). After joining the Vanderbilt faculty, he and his colleagues discovered that the majority of sRNAs on lipoproteins were not of human origin. Instead, they were derived from microbial sources: bacteria and fungi from the environment and the microbiome.
“We think that immune cells within the mucosal system are ‘sampling’ microbes from the environment, chopping up their genetic material, and loading them on lipoproteins to transport and clear them from the body,” Vickers said. “The problem is that when people have dyslipidemia, or high cholesterol levels, the LDL particles start to accumulate in tissues and blood vessels where they shouldn’t be.”
In the arterial wall, the LDL-sRNA cargo is detected by additional immune cells in the atherosclerotic lesion.
“We propose that LDL-sRNAs are being sensed as foreign pathogens and are triggering an inflammatory response that promotes atherosclerosis and cardiovascular disease,” Vickers said.
The researchers have identified receptors inside immune system macrophage cells that detect the sRNAs, and they have developed a modified sRNA drug that can block the candidate receptors. Early studies suggest that the modified sRNA therapy can reduce the development of atherosclerosis in mice prone to the disease.
With the Keck Foundation support, the team will determine how microbial sRNAs are loaded onto LDL, define the receptor-mediated response to sRNAs in macrophages, and demonstrate that microbial sRNA cargo on LDL is a major inflammatory stimulus in atherosclerosis.
If the studies are successful, blocking the sRNA stimulus may be a new treatment strategy for cardiovascular diseases as well as other inflammatory and metabolic diseases.
“The Keck Foundation award recognizes that Dr. Vickers’ discoveries could have a transformative impact on the fields of cardiovascular research, lipoproteins, macrophage biology and extracellular RNAs,” said Jennifer Pietenpol, PhD, Executive Vice President for Research at VUMC. “We are thrilled that VUMC received this highly competitive award for our investigators’ paradigm-shifting research.”
“This project is a great example of the synergy between the Departments of Medicine and Biostatistics and VUMC’s VANTAGE sequencing shared resource in developing a completely new pipeline for analyzing microbial RNAs, and now that technology is available to anyone at Vanderbilt,” Vickers said.
The Keck Foundation award joins a National Institutes of Health-funded Program Project Grant in supporting the work of the Atherosclerosis Research Unit, which welcomes new research members at all levels of training.