Mark W. Feinberg, MD, Cardiologist with Mass General Brigham Heart and the Vascular Institute and Professor of Medicine at Harvard Medical School, is the highest author of a document published in the Journal of Clinical Investigation, “A LNCRNA Muscle Muscle Cell Ischemia with MIR-143-3P/HHIP.
Q: Which question did you investigate?
What causes poor outcomes in patients with advanced peripheral artery disease developing a complication called chronic threatening ischemia (CLTI), which has a high risk of limb amputation due to the limitation of blood flow to the extremities?
For decades, many research on CTLI focused on understanding the factors coming from endothelial parameters released by cells that align our blood vessels and how these factors lead to the development of new blood vessels. (The development of new blood vessels from existing is called angiogenesis.) The idea is that if we can find a treatment that helps patients with CLTi produce more blood vessels, we can improve blood flow to endangered extremities and reduce the risk of amputation.
To date, the growth factors that have identified these studies have failed in clinical trials to improve the results. Our study shows a different approach. We have expressed factors in samples of skeletal muscles from patients with CLTi to identify those that were different compared to witnesses.
Paradoxically, they were not growth factors that appeared as different, but a long non-coding RNA (LNCRNA) called Carmn-and was not expressed in endothelial cells, only in smooth muscle cells.
Q: What methods or approach did you use?
We used a series of transcriptional profile approaches to identify LNCRNA Carmn in human skeletal muscle biopsies and models of mice.
We developed a knockout knockout from LNCRNA Carmn which showed reduced blood flow recovery, limb necrosis and amputation in a similar way to patients with CLTi who have reduced levels of expression of this LNCRNA in skeletal muscle biopsies.
Q: What did you find?
We found that a unique protein called HHIP, made of smooth muscle cells, is controlled by LNCRNA Carmn. HHIP helps to manage blood vessels, blood flow and healing of tissues.
When the HHIP was blocked-when another HHIP control molecule was increased-a gloom that increased best and the damaged tissue was more effective. This reveals a new way that collaborate together the cells of the smooth muscles and blood vessel cells, which scientists had not understood before.
Q: What was amazing for your study?
Paradoxically, despite the fact that this LNCRNA is not expressed in endothelial cells that make capillaries, mice that cannot produce this LNCRNA have reduced capillary vessels in their skeletal muscles with extremity. HHIP appears to be the missing link, connecting what happens to smooth muscle cells (SMCS) with the effects we see in endothelial cells (ECS). Suspension of HHIP or the over -expression of a microrna that regulates HHIP was sufficient to complete vascular rescue, tissue hematopoiesis and repair.
Q: What are the consequences?
The project provides new therapeutic strategies for years of threatening ischemia and provides new ideas for the SMC-EC intersection that had not been previously understood in the field of angiogenesis.
Q: What are the next steps?
We try to understand why the molecule Candy It falls when the blood flow blocks at the edges. We have found a very promising new target that carmn can control when oxygen levels are low. This could lead to new ways to enhance carmn, improve blood flow and help tissue treatment, benefiting people with various heart problems and blood vessels such as the peripheral artery and CLTI.
Source:
Magazine report:
Zhai, M., et al. (2025). An LNCRNA of smooth muscle cells controls angiogenesis in chronic ischemia threatening via MIR-143-3P/HHIP signaling. Newspaper of clinical research. Doi.org/10.1172/JCI188559
