Heart HealthEnzyme CTSL Triggers Rogue Notch1 Signaling That Drives Artery-Aging and Plaque
Scientists at the University of Pittsburgh discovered a previously unknown chain of molecular events that accelerates artery aging and plaque formation. An enzyme called cathepsin L (CTSL) directly cuts and activates the Notch1 protein without the usual cellular signal — releasing a fragment that travels to the nucleus and switches on genes that push blood vessel cells into senescence, a state of permanent growth arrest. This senescence drives atherosclerosis. In mice engineered to develop artery disease, blocking any step in this pathway — CTSL, Notch1, or the downstream gene CUX1 — dramatically reduced plaque size, protected elastic fibers in artery walls, and lowered inflammatory immune cell infiltration. Human plaque samples confirmed elevated levels of CTSL and active Notch1. The findings open a new therapeutic window for targeting cellular senescence to slow or prevent heart disease.
