Reduced expression of KCNMB1 leads to vascular smooth muscle cell phenotypic switch and apoptosis

Biochem Pharmacol. 2025 Jul 11:117151. doi: 10.1016/j.bcp.2025.117151. Online ahead of print.

Abstract

BK channel, the large conductance calcium-activated potassium channel, plays an important role in negative feedback regulation of membrane potential and relaxation in vascular smooth muscle cells (VSMCs) due to its high conductance, voltage and calcium sensitivity. However, the role of the BK channel in VSMC fate, particularly during the chronic process of cardiovascular disease (CVD) development, is not fully understood. In our study, we selected and analyzed different CVD datasets from the NCBI GEO database and indicated that KCNMB1 expression was significantly decreased in the disease group, and was positively associated with VSMC contractile and proliferative markers, and negatively associated with apoptotic markers. Additionally, primary rat aortic VSMCs were isolated and knocked down of KCNMB1 by siRNA to compare the VSMC morphology, function and indicator expression at different times. After 24 h of KCNMB1 knockdown (si24h), VSMCs changed from a long spindle shape to a polygon-like shape, contractility and contractile markers expression were significantly decreased, and migration and proliferation markers was significantly increased. After 48 h (si48h) and 72 h (si72h) of KCNMB1 knockdown, the scratch assay, TUNEL staining and apoptotic markers analysis all showed that VSMC apoptosis was significantly increased in si72h group. These results suggest that the abnormal function of VSMCs caused by the decreased expression of KCNMB1 is a dynamic process, with a switch from contractile to a proliferative and migratory phenotype and ultimately leading to apoptosis. Our findings indicate that therapies enhancing KCNMB1 expression might be a potential strategy for the prevention and treatment of CVD.

Keywords: Apoptosis; CVD; KCNMB1; Phenotypic switch; VSMC.