BNP promotes platelet activation and thrombosis via its receptor natriureticpeptide receptor-a (NPRA): A paradigm shift from biomarker to effector

Abstract Background-B-type natriuretic peptide (BNP) is a cardiac-derived vasodilator and a well-established biomarker for heart failure. Elevated BNP and its cleavage product N-terminal proBNP (NT-proBNP) also predict adverse outcomes in acute coronary syndromes. However, it remains unclear whether BNP directly contributes to cardiovascular disease pathogenesis, such as by promoting thrombosis, or is merely a biomarker. Methods-We assessed the effect of BNP on platelets in vitro and thrombosis in vivo. Platelets were incubated with BNP to measure intracellular cyclic guanosine monophosphate (cGMP) levels and platelet activation markers. BNP was injected into wild-type and NPRA-deficient mice to evaluate its effect on thrombus formation in a FeCl₃ carotid injury-induced arterial thrombosis model and a thromboplastin-induced pulmonary embolism model. BNP receptor natriuretic peptide receptor-A (NPRA) expression in platelets was determined by RT-PCR and Western blot. Results-BNP significantly elevated platelet cGMP and potentiated platelet aggregation, granule secretion, spreading, and clot retraction in vitro. In vivo, BNP administration accelerated thrombus formation in both arterial and pulmonary models in wild-type mice. These prothrombotic effects were abrogated in NPRA-deficient mice. NPRA-deficient mice exhibited impaired platelet activation, prolonged tail bleeding times, and longer occlusion times in the arterial injury model. BNP injection failed to promote thrombosis in NPRA-deficient mice. Conclusions-Our study demonstrates that BNP promotes platelet activation and enhances arterial thrombosis and thromboembolism via NPRA signaling. These findings suggest that BNP is not only a biomarker of cardiovascular disease, but also active effector contributing to thrombosis in cardiovascular disease.