Berberine inhibits proliferation and apoptosis of vascular smooth muscle cells induced by mechanical stretch via the PDI/ERS and MAPK pathways

We recently demonstrated that mechanical stretch increases the proliferation and apoptosis of vascular smooth muscle cells (VSMCs) by activating the protein disulfide isomerase (PDI) redox system, thus accelerating atherosclerotic lesion formation in the transplanted vein. At present, there are no efficient intervention measures to prevent this phenomenon. Berberine inhibits pathological vascular remodeling caused by hypertension, but the underlying mechanism is controversial. Herein, we investigate the role of berberine and the underlying mechanism of its effects on mechanical stretch-induced VSMC proliferation and apoptosis.Mouse VSMCs cultivated on flexible membranes were pretreated for 1 h with one of the following substances: berberine, PDI inhibitor bacitracin, MAPK inhibitors, or ERS inhibitor 4-PBA. VSMCs were then subjected to mechanical stretch. Immunofluorescence and western blot were used to detect proliferation and apoptosis, as well as to analyze signaling pathways in VSMCs.Our results showed that berberine inhibits the PDI-endoplasmic reticulum stress system, thereby attenuating the simultaneous increase of VSMC proliferation and apoptosis in response to mechanical stretch. Interestingly, MAPK inhibitors PD98059, SP600125, and SB202190 significantly reduced the activation of ERS signaling cascades, and their combination with berberine had additive effects. The ERS inhibitor 4-PBA reduced PDI activation and ERS signaling, but not MAPK phosphorylation. Moreover, caspase-3 and caspase-12 were downregulated by berberine.These results illustrate a novel mechanism of action of berberine that has practical implications. Our data provide important insights for the prevention and treatment of vascular remodeling and diseases caused by mechanical stretching during hypertension.