Overactivated bradykinin-B2 receptor promotes type a aortic dissection by inducing endothelial dysfunction:...

Type A aortic dissection (TAAD) is a life-threatening cardiovascular emergency for which no effective pharmacological therapy currently exists. Elevated bradykinin (BK) has been identified as an independent predictor of poor postoperative outcomes in TAAD patients. However, whether and how elevated BK contributes to TAAD pathogenesis remains unknown. Here, we aimed to delineate the mechanistic role of BK and its receptors in TAAD pathogenesis.

BK levels were measured in plasma and aortic tissues from TAAD patients and matched controls. In a β-aminopropionitrile (BAPN)-induced TAAD mouse model, selective blockade of the bradykinin B2 receptor (B2R) with icatibant was evaluated. The underlying mechanisms were further investigated in human umbilical vein endothelial cells (HUVECs) by assessing intracellular superoxide and nitric oxide (NO) levels.

BK levels were significantly elevated in TAAD patients and mice compared with controls. In the BAPN-induced model, icatibant significantly attenuated disease progression, reducing both TAAD incidence and mortality independently of blood pressure. Mechanistically, excessive BK activated endothelial B2R, which elevated intracellular superoxide levels, suppressed NO production, and ultimately resulted in endothelial damage and TAAD; icatibant reversed these changes by restoring P-VASP levels and NO bioavailability.

Our findings demonstrate that BK-driven B2R activation induces endothelial dysfunction and TAAD. Targeting this pathway with icatibant mitigates disease progression, nominating B2R inhibition as a viable pharmacological strategy against TAAD.