The oxidative-stress-driven circLyst/miR-298-5p/Col23a1 axis is established as a critical regulator of vascular remodeling, highlighting circLyst as a potential therapeutic target for hypertensive vascular disease.
Next-generation sequencing identified 165 differentially expressed circRNAs in the thoracic aortas of spontaneously hypertensive rats compared with normotensive controls.
CircLyst (circ_2465) was confirmed as a novel circular RNA resistant to RNase R degradation and stably localized in the cytoplasm of vascular smooth muscle cells.
CircLyst expression was elevated in the thoracic aortas of spontaneously hypertensive rats, in hypertensive patients, and in vascular smooth muscle cells exposed to high cyclic stretch in vitro.
Oxidative stress mediated by NADPH oxidases NOX1 and NOX4 was identified as the mechanistic driver of circLyst expression under high cyclic stretch.
CircLyst functioned as a competing endogenous RNA (ceRNA) by sponging miR-298-5p to derepress its target gene Col23a1, promoting VSMC proliferation and migration.
Both systemic and VSMC-specific targeting of circLyst attenuated pathological vascular remodeling and blunted hypertension in animal models.
This research suggests that a previously uncharacterized circular RNA molecule called circLyst plays a central role in the harmful changes that occur in blood vessel walls during hypertension (high blood pressure). When blood vessels experience abnormally high mechanical stretching forces — as happens with elevated blood pressure — cells in the vessel walls generate oxidative stress through specific enzymes (NOX1 and NOX4), which in turn causes circLyst levels to rise. The researchers observed this pattern in rat models of hypertension, in human hypertensive patients, and in laboratory cell experiments, establishing that the phenomenon is relevant across species and in human disease. CircLyst works by acting as a molecular 'sponge,' soaking up a small regulatory RNA molecule called miR-298-5p. Normally, miR-298-5p suppresses a gene called Col23a1 (which encodes a type of collagen protein), but when circLyst sequesters miR-298-5p, Col23a1 activity increases. Higher Col23a1 activity encourages the smooth muscle cells of blood vessels to multiply and move — behaviors that drive the thickening and stiffening of blood vessel walls seen in hypertension. When the researchers blocked circLyst — either throughout the entire animal or specifically within vascular smooth muscle cells — pathological vessel wall changes were reduced and blood pressure was lowered in animal models. This research suggests that the circLyst/miR-298-5p/Col23a1 molecular pathway is a previously unknown link between the physical forces of high blood pressure and the damaging structural changes in blood vessels. Because targeting circLyst reduced both vascular remodeling and blood pressure in animals, it may represent a novel therapeutic target for treating hypertension and related cardiovascular complications, though further research in humans would be needed.
Tan J, Hu W, Shen L, Luo B, Liu H, Li F, et al.. (2026). Mechanotransduction through oxidative stress upregulates circLyst to drive vascular remodeling in hypertensive humans and rodents.. Molecular biomedicine. https://doi.org/10.1186/s43556-026-00593-3