Their findings in human tissue and confirmed in rodent models of vascular disease, provide new insight into how smooth muscle cells in our blood vessel walls go from enabling a sound passageway for blood flow to instead enabling plaque development in places like our coronary arteries and/or reclosure of those arteries following common treatments including angioplasty and stent placement.
They also potentially point to a new approach to avoiding both, that could one day include adding CARMN to drug-eluting stents, which are currently coated with antiproliferative drugs to help deter the unhealthy cell proliferation and scar formation that may result from their placement.
“If you have a low level of CARMN, it mostly likely predisposes you to a higher susceptibility to get atherosclerosis or angioplasty- induced restenosis,” says Dr. Jiliang Zhou, vascular biologist in the Department of Pharmacology and Toxicology at the Medical College of Georgia at Augusta University. “If CARMN is downregulated, it will induce or trigger those smooth muscle cells to become unhealthy or diseased.”
When the scientists restored healthy CARMN levels in models of common vascular disease, unhealthy cell proliferation and scar formation inside blood vessels were dramatically diminished, and when they removed CARMN from smooth muscle cells, the damage response was exaggerated, leaving little room for blood to flow, they report in the journal Circulation. Many of us likely think about RNA making proteins, and which proteins the RNA makes determine a gene’s function. Less-studied noncoding RNAs don’t make proteins but do help regulate cells, and have been shown to have a role in many different normal body functions as well as disease states like cancer. So the scientists decided to look at what was happening with long noncoding RNA in vascular disease and that’s where CARMN stood out.
Senior postdoctoral fellow Dr. Kunzhe Dong, the study’s first author, led analysis of large-scale human datasets of RNA sequencing of multiple tissue and cell types to find the long-noncoding RNAs — literally the longest of the noncoding RNAs — that were abundant in smooth muscle cells and might have a role in their activity. The datasets enabled them to compare expression in healthy and changed, or modulated, cells in a single individual.
CARMN emerged as the sole long noncoding RNA consistently abundant in human smooth muscle cells, and subsequent studies of mouse tissues showed the same. Inside those cells, corresponding author Zhou and his colleagues saw CARMN bind to and increase the activity of myocardin, a protein and potent activator of genes critical to the differentiation of smooth muscle cells.
“They need each other to potentiate the function of each other,” Zhou says. CARMN is the first non-coding RNA found to interact with myocardin in a relationship that appears specific and essential to smooth muscle cells."
https://www.eurekalert.org/news-releases/940155CARMN Is an Evolutionarily Conserved Smooth Muscle Cell–Specific LncRNA That Maintains Contractile Phenotype by Binding Myocardin
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.121.055949We identified CARMN, which was initially annotated as the host gene of the MIR143/145 cluster and recently reported to play a role in cardiac differentiation, as a highly abundant and conserved, SMC-specific long noncoding RNA. Analysis of the Carmn GFP knock-in mouse model confirmed that Carmn is transiently expressed in embryonic cardiomyocytes and thereafter becomes restricted to SMCs. We also found that Carmn is transcribed independently of Mir143/145. CARMN expression is dramatically decreased by vascular disease in humans and murine models and regulates the contractile phenotype of VSMCs in vitro. In vivo, SMC-specific deletion of Carmn significantly exacerbated, whereas overexpression of Carmn markedly attenuated, injury-induced neointima formation in mouse and rat, respectively. Mechanistically, we found that Carmn physically binds to the key transcriptional cofactor myocardin, facilitating its activity and thereby maintaining the contractile phenotype of VSMCs.
Conclusions:
CARMN is an evolutionarily conserved SMC-specific long noncoding RNA with a previously unappreciated role in maintaining the contractile phenotype of VSMCs and is the first noncoding RNA discovered to interact with myocardin"
