Molecular pathogenesis of pulmonary arterial hypertension

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PROJECT SUMMARY/ABSTRACT Pulmonary Arterial Hypertension (PAH) is a rare disease characterized by the progressive remodeling of pulmonary arteries (PAs). It is incurable and leads to death from right ventricular heart failure in 3 years if untreated. Heterozygous mutations of the bone morphogenetic protein type 2 receptor gene (BMPR2) are the leading genetic cause of both heritable and non-heritable PAH. Compared to patients without BMPR2 mutations, PAH patients with BMPR2 mutations develop a more severe form of PAH at least 10 years earlier. Despite the progress in understanding the molecular and cellular processes mediating occlusive remodeling of PAs as a result of BMPR2 mutations, a targeted therapy does not yet exist, and BMPR2 carrier patients remain at high risk of requiring transplantation and succumbing to the disease. There is a dire need of novel therapies for BMPR2 mutation patients. Our studies demonstrated increased DNA damage in both idiopathic- and heritable-PAH patients, suggesting genotoxic stress is a risk factor for PAH, but significant knowledge gaps persist, as follows: (i) whether the loss of genome integrity is the cause or the consequence of PAH, (ii) the cell type in which DNA damage occur, (iii) a potential link between BMPR2 mutations and DNA damage, and (iv) the molecular mechanism of DNA damage in PAH. We found that BMPR2 and its downstream signaling pathway are essential to protect genome integrity in pulmonary artery endothelial cells (PAECs), and they act by maintaining a key component of the DNA repair pathway: Rad51. Inactivation of BMPR2 results in reduction of Rad51, leading to accumulation of DNA damage in PAECs. Attenuation of Rad51 was measured in the endothelium of both animal models of PAH and human patients. On the contrary, activation of the BMPR2 signaling pathway by BMP9 restores Rad51 and prevents the accumulation of DNA damage in PAECs. The main hypothesis we will test is that PAECs undergoing genotoxic stress develop a pathological remodeling and PAH. The objective of this application is to develop a strategy to restore the DNA repair system in PAECs and prevent or inhibit the progression of vascular remodeling, as a novel therapy for PAH with a defective BMP signal. The forthcoming results from this application will provide important insights into developing a novel therapeutic strategy for PAH.