Formononetin Relieves Chronic Stress-related Neointimal Hyperplasia in Mice by Regulating HDAC6

Abstract

Chronic stress severely impairs physical and mental health and is a critical risk factor for cardiovascular diseases. Formononetin (FMN) has shown promising cardiovascular protective effects, yet its functional role and molecular mechanism in chronic stress-triggered arterial neointimal hyperplasia and concomitant mood disturbances remain poorly elucidated. Herein, network pharmacology was used to predict the underlying mechanisms of FMN against cardiovascular disease-depression comorbidity. A total of 111 overlapping targets were screened out, and functional enrichment combined with molecular docking analyses revealed that FMN mainly regulates inflammation, apoptosis and autophagy via binding to core hub proteins. A dual mouse model recapitulating chronic stress and carotid artery injury was subsequently established for in vivo validation for experimental validation. The results demonstrated that chronic stress aggravated arterial intimal hyperplasia and aortic senescence, and induced anxiety- and depression-like behaviors. FMN treatment notably improved emotional disorders, reduced HDAC6 expression, activated autophagy, inhibited apoptosis, and alleviated intimal thickening. Moreover, the HDAC6 inhibitor TubA recapitulated the vascular protection of FMN. In conclusion, FMN attenuates chronic stress-induced vascular injury and emotional dysfunction via suppressing HDAC6 signaling to restore autophagy and inhibit inflammation and apoptosis. This study unveils the dual cardio-neuroprotective capacities of FMN and provides novel mechanistic insights for the treatment of chronic stress-related cardiocerebral comorbidities.