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

IF 10.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Priya Murugesan, Yuhan Zhang, Yixuan Zhang, Ji Youn Youn, Hua Cai
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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.
netrin -1衍生、修饰和改进的小肽治疗肺动脉高压的新方法
肺动脉高压(PH)是一种严重和致命的心肺疾病,有效阻止或减缓疾病发展的治疗选择有限。我们之前已经证明netrin-1通过适度和稳定的一氧化氮(NO)的产生和氧化应激的衰减来保护心脏免受损伤。鉴于一氧化氮缺乏和氧化应激在PH发病中的中间作用,我们最近发现netrin-1和netrin-1衍生的小肽对PH有新的有效的减弱作用。目前,我们研究了通过修饰netrin-1衍生肽对PH的治疗作用,以增加其稳定性、渗透性和抗氧化应激性,这有望改善PH的缓解效果。事实上,V1P、V2P、V3P、V1S、V1T、V1D、V1C修饰肽在显著或完全缓解缺氧暴露小鼠PH的所有病理生理和分子特征方面,被证明是更优越或更强大的。肽V1S和V1C将mPAP和RVSP降低到基线水平以下。所有修饰肽都比netrin-1和原始肽更有效地完全减轻右心肥厚。它们在消除特征性血管重构(内侧增厚、肌肉化、细胞增殖和纤维化增加)以及总ROS和线粒体超氧化物的产生方面也更有效。eNOS解偶联活性被修饰肽消除,同时NO生物利用度恢复。综上所述,这些新发现表明,修饰的netrin-1衍生的小肽在治疗PH方面具有优势,在减弱PH的所有机制途径和标志表型方面具有改善或更强大的作用。由于这些修饰的肽处理特性更容易交付,具有更高的稳定性和可用性,它们可能更容易转化为临床实践,用于治疗急需新疗法的PH。
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来源期刊
Redox Biology
Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
19.90
自引率
3.50%
发文量
318
审稿时长
25 days
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.
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