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Publications of the Week

A Macrophage-Specific lncRNA Regulates Apoptosis and Atherosclerosis by Tethering HuR in the Nucleus

By December 11, 2020No Comments

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This week we profile a recent publication in Nature Communications from the
laboratory of Dr. Mark Feinberg (pictured) at Brigham and Women’s Hospital.

What is the significance of the findings in this publication?

All our protein-coding genes comprise only about 2% of the entire genome, leaving a vast universe of other transcripts, the majority of which constitute non-coding RNAs. These are not passive junk sequences, but are actively transcribed transcripts that just don’t make a protein. It’s estimated there are up to 50,000 long non-coding RNAs or lncRNAs for short. These lncRNAs can bind to RNA, DNA, and proteins providing new levels of regulation that we need to think about in the pathogenesis of cardiovascular disease and a range of disease states. We hypothesized that there may be lncRNAs that may be highly expressed in the blood vessel wall during the process of atherosclerosis, a major contributor to cardiovascular death, heart attacks and strokes and peripheral vascular disease.

In this study, we peeled off the innermost lining of the blood vessel wall and performed RNA sequencing to discover what are the lncRNAs with atherosclerosis progression and regression.

  1. We identified a lncRNA termed MAARS (for Macrophage-Associated Atherosclerosis lncRNA Sequence) that is expressed specifically in macrophages in atherosclerotic plaques and contributes to progression of disease. Macrophages are a specialized type of white blood cell in the immune system that are involved in patrolling and cleaning up invading pathogens, cellular debris, and anything else that might be considered foreign in a process turned phagocytosis. In this sense, you can think about these macrophages playing a role similar to PACMAN. They also initiating adaptive immunity by recruiting other cell types like lymphocytes. They also are involved in innate immunity that’s our 1st line of defense
  2. Expression of MAARS is increases by 270-fold with atherosclerotic progression and decreases with regression by 60%.
  3. Therapeutic neutralization of MAARS reduced atherosclerotic lesion formation by 52% by decreasing macrophage apoptosis (cells that are dying) and increasing efferocytosis (the clearance of dead cellular debris) from the lesions. Remarkably, these effects were largely independent of effects on circulating cholesterol.
  4. Mechanistically, in the vessel wall MAARS biophysically interacts with the RNA-binding protein HuR, a critical mediator of apoptosis. Knockdown of MAARS alters HuR nuclear-to-cytosolic shuttling and HuR target genes involved in apoptosis.

These findings reveal a novel role for this lncRNA in regulating macrophage apoptosis in the vessel wall and has implications for atherosclerosis and other chronic vascular disease states.

What are the next steps for this research?

Related to this research study, we will explore the roles of a human homologue of this lncRNA and its interacting protein HuR as potential therapeutic targets in human macrophages and human atherosclerotic sample sets for translational relevance. More broadly, we are working on several non-coding RNAs (both lncRNAs and microRNAs) in the progression and regression phases of atherosclerosis to identify new clues for potential targets and signaling pathways that may be involved. We have a particular interest in understanding accelerated atherosclerosis that occurs with diabetes, which remains a common cardiovascular risk factor in our patients. We’ve developed new tools to capture non-coding RNA interactions directly in the blood vessel wall which makes this field exciting for exploring mechanism.

This work was funded by:

The NIH and AHA

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