Researchers at Vanderbilt University Medical Center are connecting the dots between circulating pieces of non-coding microbial small RNA (sRNA) and heightened inflammation in the arterial wall lining, abetting atherosclerosis.
Recent results of the CANTOS trial show that targeting inflammation can reduce cardiovascular events, but there is an increase in severe infection. Currently, one of the biggest questions is how to target the inflammatory component of atherosclerosis without compromising proper immune function.
Armed with a $1 million grant from the W.M. Keck Foundation, the team, led by Kasey Vickers, Ph.D., assistant professor of medicine and molecular physiology and biophysics, is working to understand the inflammatory function of sRNA. They hope to describe its contribution to the observed residual inflammatory risk for cardiovascular disease in subjects with effectively managed LDL-cholesterol levels.
“We want to go after the stimuli for this inflammation, these bacterial RNA bits, as opposed to downstream inflammatory cytokine mediators, and determine how to stop the process, at the receptor level, to reduce atherosclerotic burden,” Vickers said.
A Seminal Discovery
While at the NIH, Vickers and his coworkers discovered lipoproteins carry human microRNAs in the blood. At Vanderbilt, he is working with director of Vanderbilt Lipid Clinic and Atherosclerosis Research Unit, MacRae F. Linton, M.D.; research instructor Ryan M. Allen, PhD.; biostatistician Quanhu Sheng, PhD.; and a team of bench scientists, clinicians, and informaticists to determine the functional impact of microbial sRNAs on LDL in atherosclerosis.
This team made the surprising discovery that the majority of sRNAs on lipoproteins, including LDL, are foreign, coming mainly from bacteria in our environment and microbiome. This led to the hypothesis that foreign cargo on LDL induces an inflammatory immune response complicit in plaque development.
“Since many pieces were microbial in origin, we started asking questions about what macrophages in atherosclerotic lesions do when they encounter these foreign sRNAs. The answer is, they freak out!” Vickers said.
Inflammation Begets Inflammation
The immune response to LDL-sRNA exacerbates the inflammatory process at work in the arterial wall, which then becomes less efficient at shedding the accumulated lipids. This can lead to occlusion and/or plaque rupture.
“Although LDL-cholesterol lowering with statins is a highly effective way to reduce heart attack and stroke, a significant proportion of patients still have cardiovascular events. This has been referred to as ‘residual inflammatory risk,’” Linton said. “Understanding and treating this has the potential to further reduce their risk of cardiovascular events.”
The team has a drug they believe can inhibit certain receptors on macrophages, (endosomal toll-like receptors 7 and 8), to prevent them from eliciting an immune response to the microbial LDL-sRNAs. “Since anti-inflammatories that target cytokines and other downstream components aren’t a sustainable treatment, we want to go after the stimulus instead,” Vickers said.
Vickers’ team has three primary aims for the new research:
- Determine the sources of the bacterial RNA. Is it through the gut, from our diet, through the lung from the air we breathe? What cell types in the mucosal lining are involved in moving the RNA from bacteria to lipoproteins?
- Verify that receptors 7 and 8 are the ones mediating the inflammatory response to sRNA carried by LDL.
- Demonstrate that the sRNAs are the inflammatory cargo, explore what makes them inflammatory and determine whether they can be chemically modified.
Vickers and his team will determine the impact of their drug on reducing disease progression and inducing lesion regression in specific mouse models of atherosclerosis. They will also analyze human LDL to identify critical features of microbial sRNAs in people with cardiovascular disease. They will examine LDL-sRNAs signatures of people from different environments and cardiovascular disease states. The work could help propel a receptor-blocking drug to clinical trials.