Development of a therapeutic anti-marinobufagenin antibody

National Institute On Aging

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Abstract

We studied 16 patients with PE (mean BP = 1232 mmHg;282 years, 36 weeks gest. age) and 14 gestational age-matched normal pregnant subjects (mean BP = 922 mmHg). PE was associated with a rise in plasma and placental levels of MBG. In PE umbilical arteries, the expression of Fli-1, a transcription factor and a negative regulator of fibrosis, was significantly reduced (P<0.001), while procollagen-1 expression was increased (P<0.01). As compared to control vessels, isolated rings of umbilical arteries from subjects with PE demonstrated unaltered responsiveness to endothelin-1 (EC50 = 2.2 and 3.2 nmol/L, respectively), but exhibited an impaired response to the relaxant effect of sodium nitroprusside (EC50= 1.5 vs. 32.4 nmol/L P<.001) following endothelin-1-induced constriction. Ex vivo treatment of normal umbilical arteries explants with 1 and 10 nmol/L MBG mimicked the effects of PE, specifically suppressed Fli-1 and increased collagen-1 expression while impairing vasorelaxation. Our results indicate that in PE, elevated levels of MBG induce vascular fibrosis via a Fli-1-dependent mechanism which leads to an impairment of vasorelaxation, and suggest that MBG represents a potential target for therapy of this syndrome.