Poly ADP‐Ribose polymerase (PARP‐1) and DNA damage in pulmonary arterial hypertension

Abstract

Pulmonary arterial (PA) hypertension (PAH) is characterized by PA obstruction, associated with oxidative stress and inflammation sustained by NFAT (Nuclear factor of activated T‐cells) and HIF‐1 (Hypoxia inducible factor 1) activation. Despite these DNA damaging conditions, PAH‐PA smooth muscle cells (PASMC) are proliferative and apoptosis‐resistant, suggesting DNA repair machinery activation. PARP‐1 is a crucial enzyme implicated single strand DNA breaks (SSB) repair and regulates cell survival and expression of many genes such as NFAT and HIF‐1. We hypothesized that PARP‐1 is activated in PAH‐PASMC, inducing proliferation and survival and thus PA remodeling. Using human lung tissues and PASMC, we demonstrated that increased oxidative stress promotes SSB in PAH‐PASMC. Increased SSB triggers PARP‐1 activation, which promotes NFAT/HIF activation, increasing PAH‐PASMC proliferation and resistance to apoptosis. Finally, we showed that clinically available PARP inhibitor ABT‐888 reverses all these abnormalities both in vitro and in vivo in rats with monocrotaline and Sugen‐induced PAH. In conclusion, we demonstrated the implication of DNA repair machinery PARPs in PAH etiology and that clinically available PARP‐1 inhibitors represent new therapeutic agents for PAH treatment.A Canadian Thoracic Society scholarship to JM and Canadian Institutes of Health Research grants to SB supported this work.