Novel RNA Target shows Promise for Treating Chronic Limb Ischemia

A new study published in the Journal of Clinical Investigation (Zhai, M., et al. 2025) has identified a long non-coding RNA (lncRNA) called CARMN as a potential therapeutic target for chronic limb-threatening ischemia (CLTI), a condition where severely reduced blood flow to the limbs can lead to amputation. The research offers a fresh approach to stimulating blood vessel growth – a process known as angiogenesis – in CLTI patients,moving beyond previous unsuccessful attempts focused on growth factors.

Historically, clinical trials testing growth factors to improve blood flow in CLTI patients have failed to deliver positive results. This prompted researchers to investigate other factors present in skeletal muscle samples from CLTI patients compared to healthy controls. Surprisingly, the study revealed that differences weren’t found in growth factors, but in the expression of the lncRNA CARMN, which is uniquely expressed in vascular smooth muscle cells, not endothelial cells.

Researchers utilized transcriptomic profiling to identify CARMN in both human skeletal muscle biopsies adn mouse models of limb ischemia. Crucially, they developed a knockout mouse lacking the CARMN lncRNA.These mice exhibited impaired blood flow recovery, limb necrosis, and ultimately, amputation – mirroring the outcomes observed in CLTI patients with reduced CARMN expression.

The study pinpointed a key mechanism: CARMN regulates a protein called HHIP, produced by smooth muscle cells, which plays a critical role in blood vessel growth, blood flow, and tissue healing. blocking HHIP, or increasing the levels of a microRNA that controls HHIP, resulted in improved blood vessel growth and more effective tissue repair. This discovery highlights a previously unknown interaction between smooth muscle cells and blood vessel cells.

“HHIP appears to be the missing link, connecting whatS happening in smooth muscle cells (SMCs) to the effects we see in endothelial cells (ECs),” the researchers noted. Inhibition of HHIP or overexpression of a microRNA regulating HHIP was sufficient to fully restore angiogenesis, limb tissue perfusion, and repair in the mouse model.

The findings suggest new therapeutic strategies for CLTI and provide valuable insights into smooth muscle-endothelial cell communication during angiogenesis. Currently, the research team is investigating the reasons behind the decrease in CARMN levels when blood flow is restricted in the limbs, focusing on a potential target that may control CARMN expression under low oxygen conditions.The ultimate goal is to develop methods to boost CARMN levels, improve blood flow, and promote tissue healing, potentially benefiting individuals with peripheral artery disease and CLTI, as well as other heart and blood vessel problems.

Source: Zhai, M., et al. (2025). A smooth muscle cell lncRNA controls angiogenesis in chronic limb-threatening ischemia through miR-143-3p/HHIP signaling. Journal of Clinical Investigation. doi.org/10.1172/jci188559.