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Bone Morphogenetic Protein 9 is a Mechanistic Biomarker of Portopulmonary Hypertension. American journal of respiratory and critical care medicine Nikolic, I., Yung, L., Yang, P., Malhotra, R., Paskin-Flerlage, S. D., Dinter, T., Bocobo, G. A., Tumelty, K. E., Faugno, A. J., Troncone, L., McNeil, M. E., Huang, X., Coser, K. R., Lai, C. S., Upton, P. D., Goumans, M. J., Zamanian, R. T., Elliott, C. G., Lee, A., Zheng, W., Berasi, S. P., Huard, C., Morrell, N. W., Chung, R. T., Channick, R. W., Roberts, K. E., Yu, P. B. 2018

Abstract

RATIONALE: Bone Morphogenetic Protein 9 (BMP9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors and downstream effectors have been reported in heritable PAH.OBJECTIVES: We sought to determine how an acquired deficiency of BMP9 signaling might contribute to PAH.METHODS AND RESULTS: Plasma levels of BMP9 and antagonist soluble Endoglin (sEng) were measured in Group 1 PAH, Group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH. BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) vs. healthy controls, or other etiologies of PAH or PH, distinguished PoPH from patients with liver disease without PAH, and was an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of BMP9 ligand trap ALK1-Fc exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia vs. hypoxia alone.CONCLUSIONS: BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH.

View details for PubMedID 30312106