DUAL INHIBITION OF BMP10 HOMODIMERS AND BMP9/10 HETERODIMERS AS A NOVEL THERAPEUTIC STRATEGY FOR SYSTEMIC HYPERTENSIVE DISEASE

Objective: Despite the availability of various antihypertensive medications, some patients experience treatment-resistant hypertension, where existing drugs fail to adequately control blood pressure. There is a pressing need for antihypertensive agents that operate through mechanisms distinct from those of current therapies. This study investigates the roles of BMP9 and BMP10, which have been genetically linked to pulmonary arterial hypertension, in the context of systemic hypertension. We aim to explore the therapeutic potential of neutralizing antibodies against BMP9 and BMP10 for treating systemic hypertension. Design and method: Neutralizing antibodies specific to BMP9 and BMP10 were generated. We developed sandwich ELISA and cell-based reporter assays to detect BMP9 homodimers, BMP10 homodimers, and BMP9/10 heterodimers. Telemetry studies in rats were conducted to assess the antihypertensive effects of these antibodies. Furthermore, the therapeutic efficacy of the antibody was evaluated in Dahl salt-sensitive rats fed a high-salt diet. Blood pressure, proteinuria, albuminuria, and echocardiographic assessments were performed to evaluate cardiac and renal protective effects. Histopathological examinations were conducted to assess organ damage. Results: We produced three types of neutralizing antibodies targeting BMP9 and BMP10, confirming their specificity and blocking activity through cell-based assays. Sandwich ELISA revealed the presence of BMP9/10 heterodimers in human serum. In vivo studies in normotensive rats indicated that BMP10 homodimers and BMP9/10 heterodimers, but not BMP9 homodimers, significantly influence systemic blood pressure regulation. The antibody clone A, which neutralizes BMP10 homodimers and BMP9/10 heterodimers, resulted in a significant and sustained reduction in blood pressure in spontaneously hypertensive rats (SHR). Furthermore, clone A normalizing blood pressure and alleviating cardiac and renal impairment in Dahl salt-sensitive rats. Conclusions: Our findings suggest that BMP10 homodimers and BMP9/10 heterodimers contribute to the pathogenesis of hypertensive disease. BMP10 operates through a distinct mechanism from known vasoactive hormones. Neutralizing antibodies targeting BMP10 homodimers and BMP9/10 heterodimers may serve as novel therapeutic agents for managing treatment-resistant hypertension.