Biology of Monocrotaline Induced Pulmonary Hypertension

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Monocrotaline (MCT) induced pulmonary hypertension remains a principle model for the biology and development of intervention strategies for the human disease. Current concepts of pulmonary hypertension (PH) assign a primary pathogenetic role to the pulmonary endothelial cell in both human PH and that induced by MCT. Recently, a genetic lesion in the Bone Morphogenic Protein Receptor (BMPR) has been identified in humans with pulmonary hypertension The overall objective of this grant is to characterize the effects of MCT on the biology of the pulmonary endothelial cell and relate them to the initiating mechanisms of PH. Our previous work has demonstrated that several proteins with potential functional significance for endothelial cells have selective covalent interactions with the reactive intermediate of MCT metabolism, monocrotaline pyrrole (MCTP). This leads to our hypothesis that protein targets of MCT initiate vascular remodeling by altering endothelial cell function similar to endothelial dysfunction in persons with genetic susceptibility to primary pulmonary hypertension. Our specific aims are to further characterize the protein targets of MCT, to determine the functional significance of protein binding in endothelial cells, to evaluate proteins regulating endothelial cell barrier function as potential MCT targets and to determine whether the MCT model alters the BMPR signal pathway affected in humans with PH.