nutlin-3a and Pulmonary-Arterial-Hypertension

In pulmonary arterial hypertension (PAH), endothelial dysfunction and obliterative vascular disease are associated with DNA damage and impaired signaling of BMPR2 (bone morphogenetic protein type 2 receptor) via two downstream transcription factors, PPARγ (peroxisome proliferator-activated receptor gamma), and p53.. We investigated the vasculoprotective and regenerative potential of a newly identified PPARγ-p53 transcription factor complex in the pulmonary endothelium.. In this study, we identified a pharmacologically inducible vasculoprotective mechanism in pulmonary arterial and lung MV (microvascular) endothelial cells in response to DNA damage and oxidant stress regulated in part by a BMPR2 dependent transcription factor complex between PPARγ and p53. Chromatin immunoprecipitation sequencing and RNA-sequencing established an inducible PPARγ-p53 mediated regenerative program regulating 19 genes involved in lung endothelial cell survival, angiogenesis and DNA repair including,. We identified a novel therapeutic strategy that activates a vasculoprotective gene regulation program in PAECs downstream of dysfunctional BMPR2 to rehabilitate PAH PAECs, regenerate pulmonary microvessels, and reverse disease. Our studies pave the way for p53-based vasculoregenerative therapies for PAH by extending the therapeutic focus to PAEC dysfunction and to DNA damage associated with PAH progression.

Topics: Angiogenesis Inducing Agents; Animals; Bone Morphogenetic Protein Receptors, Type II; Cells, Cultured; Endothelial Cells; Female; Gene Expression Regulation; Humans; Imidazoles; Male; Mice; Mice, Knockout; Neovascularization, Physiologic; Oxidative Stress; Piperazines; PPAR gamma; Pulmonary Arterial Hypertension; Pulmonary Artery; Regeneration; Signal Transduction; Tumor Suppressor Protein p53