Mechanism and Application of Prothymosin Α Gene Delivery in Flow-Induced Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) specifies the primary lesion in the pulmonary arterial system caused by genetic defect such as congenital heart diseases, bone morphogenetic protein receptor type II (BMPR2) mutation, drug-induced portal hypertension, and others. PAH affects an estimated 15–60 per million of the population. Moreover, nearly 30% of congenital heart patients developed PAH, due to the high pulmonary vascular flow from intra-cardiac shunts, according to the European Hear survey from 1998 to 2004. Among those with congenital heart defects, the presence of PAH adversely impacts the quality of life and long-term survival. In the modern era of well-developed medication for PAH, there is still an increased risk of procedure or surgery for atrial septal defect with significant PAH. Pathologic findings of PAH in patients, as well as pulmonary hypertension (PH) in animal models, are characterized by presence of perivascular capillary formation with media thickening in pulmonary arterioles. Inflammatory cytokines, chemokines and oxidative stress play important roles in stimulating remodeling of the pulmonary arteries. The pulmonary endothelial cells and vascular smooth muscle cells (VSMCs) are activated in the vicious cycle of vessel remodeling. The applicants’ previous study and literature showed that attenuation of oxidative stress protects endothelial cells from dysfunction in flow-induced PH. Anti-oxidant enzymes such as heme oxygenase-1 (HO-1) are mediated by nuclear factor-erythroid 2-related factor 2/antioxidant responsive element (Nrf2/ARE). Prothymosin α (ProT) liberates Nrf2 from the degradation complex, which leads to expression of Nrf2/ARE dependent genes. Moreover, the applicants’ previous study showed that ProT gene transfer using adenoviral vectors attenuated atherosclerotic plaque formation in ApoE-/- mice. ProT is a highly conserved polypeptide in eukaryocytes that is involved in multiple cellular processes such as proliferation, survival, anti-apoptosis and others. ProT inhibits transforming growth factor (TGF)- signal transduction which is an important mediator in pulmonary artery remodeling induced by PH. Investigation for novel therapies are limited in English literature. This underscores the need for a continued search for novel therapies. Gene therapy effects for flow-induced PAH in human, or flow-induced PH in animal models, has yet to be elucidated. The applicant aims to explore, using adenoviral vectors for ProT gene transfer, a novel therapeutic option for flow-induced PAH.