Priya Murugesan, Yuhan Zhang, Yixuan Zhang, Ji Youn Youn, Hua Cai
{"title":"Novel and superior treatment of pulmonary hypertension with netrin-1 derived, modified and improved small peptides","authors":"Priya Murugesan, Yuhan Zhang, Yixuan Zhang, Ji Youn Youn, Hua Cai","doi":"10.1016/j.redox.2025.103710","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103710"},"PeriodicalIF":10.7000,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Redox Biology","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S221323172500223X","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease.
Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.