Novel and superior treatment of pulmonary hypertension with netrin-1 derived, modified and improved small peptides

Abstract

Pulmonary hypertension (PH) is a severe and lethal cardiorespiratory disorder with limited therapeutic options to effectively stop or regress the development of the disease. We have previously demonstrated that netrin-1 protects against cardiac injuries via modest and stable production of nitric oxide (NO) and attenuation of oxidative stress. In view of the intermediate roles of NO deficiency and oxidative stress in the pathogenesis of PH, we have recently shown novel and potent attenuating effects on PH of netrin-1 and netrin-1 derived small peptides. Currently, we investigated therapeutic effects on PH of netrin-1 derived peptides with modifications to increase their stability, permeability and resistance to oxidative stress, which are anticipated to have improved efficacies in alleviating PH. Indeed, modified peptides of V1P, V2P, V3P, V1S, V1T, V1D, V1C turned out to be superior or more robust in alleviating all of the pathophysiological and molecular features of PH in hypoxia exposed mice either substantially or completely, with peptides V1S and V1C attenuating both mPAP and RVSP to below baseline levels. All modified peptides completely attenuated right heart hypertrophy more effectively than netrin-1 and the original peptides. They were also more effective in abrogating characteristic vascular remodeling (medial thickening, muscularization, increases in cell proliferation and fibrosis), and production of total ROS and mitochondrial superoxide. eNOS uncoupling activity was abolished by the modified peptides, which was accompanied by restoration in NO bioavailability. Taken together, these novel findings demonstrate that modified, netrin-1 derived small peptides are superior in treating PH, with improved or more robust effects in attenuating all of the mechanistic pathways and hallmark phenotypes of PH. Since these modified peptides pocess properties being more easily deliverable with enhanced stability and availability, they might be more readily translatable to clinical practice for the treatment of PH for which new therapeutics are urgently in need.