PPARγ-p53-Mediated Vasculoregenerative Program to Reverse Pulmonary Hypertension.

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Genetics

Background:

• Pulmonary arterial hypertension (PAH) involves endothelial dysfunction and vascular disease, linked to DNA damage and impaired BMPR2 signaling.
• Key downstream transcription factors PPARγ and p53 are crucial in BMPR2 signaling pathways.

Purpose of the Study:

• To investigate the vasculoprotective and regenerative potential of a newly identified PPARγ-p53 transcription factor complex in pulmonary endothelium.
• To explore a novel therapeutic strategy for PAH targeting endothelial cell dysfunction.

Main Methods:

• Identified a pharmacologically inducible PPARγ-p53 complex in pulmonary microvascular endothelial cells under stress.
• Utilized ChIP-sequencing and RNA-sequencing to define the PPARγ-p53 mediated regenerative gene program.
• Studied endothelial cell-specific Bmpr2-knockout mice and PAH patient-derived cells.

Main Results:

• A PPARγ-p53 complex regulates 19 genes involved in endothelial cell survival, angiogenesis, and DNA repair.
• Disrupting the complex or reducing BMPR2 impaired gene expression in response to oxidative stress.
• Nutlin-3 treatment in mice restored p53 and PPARγ-p53 complex formation, regenerating pulmonary microvessels and reversing PAH.
• In PAH patient cells, inducing p53 and PPARγ-p53 repaired DNA damage via nucleotide excision repair without causing apoptosis.

Conclusions:

• A novel therapeutic strategy activates a vasculoprotective gene program downstream of BMPR2 in pulmonary artery endothelial cells (PAECs).
• This approach rehabilitates PAH PAECs, regenerates pulmonary microvessels, and reverses PAH.
• The findings support p53-based vasculoregenerative therapies for PAH, focusing on PAEC dysfunction and DNA damage.