From the Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences (C.N., G.B.), University of Campania Luigi Vanvitelli, Naples, Italy.
Clinical Department of Internal Medicine and Specialistic Units AOU (C.N., G.B.), University of Campania Luigi Vanvitelli, Naples, Italy.
Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):653-664. doi: 10.1161/ATVBAHA.118.312262.
In pulmonary arterial hypertension (PAH), the Warburg effect (glycolytic shift) and mitochondrial fission are determinants of phenotype alterations characteristic of the disease, such as proliferation, apoptosis resistance, migration, endothelial-mesenchymal transition, and extracellular matrix stiffness. Current therapies, focusing largely on vasodilation and antithrombotic protection, do not restore these aberrant phenotypes suggesting that additional pathways need be targeted. The multifactorial nature of PAH suggests epigenetic changes as potential determinants of vascular remodeling. Transgenerational epigenetic changes induced by hypoxia can result in permanent changes early in fetal development increasing PAH risk in adulthood. Unlike genetic mutations, epigenetic changes are pharmacologically reversible, making them an attractive target as therapeutic strategies for PAH. This review offers a landscape of the most current clinical, epigenetic-sensitive changes contributing to PAH vascular remodeling both in early and later life, with a focus on a network medicine strategy. Furthermore, we discuss the importance of the application (from morphogenesis to disease onset) of molecular network-based algorithms to dissect PAH molecular pathobiology. Additionally, we suggest an integrated network-based program for clinical disease gene discovery that may reveal novel biomarkers and novel disease targets, thus offering a truly innovative path toward redefining and treating PAH, as well as facilitating the trajectory of a comprehensive precision medicine approach to PAH.
在肺动脉高压（PAH）中，瓦博格效应（糖酵解转移）和线粒体分裂是决定疾病特征性表型改变的因素，如增殖、抗凋亡、迁移、内皮-间充质转化和细胞外基质硬度。目前的治疗方法主要集中在血管扩张和抗血栓保护上，并不能恢复这些异常表型，这表明需要针对其他途径。PAH 的多因素性质表明表观遗传变化可能是血管重塑的潜在决定因素。缺氧引起的跨代表观遗传变化可导致胎儿发育早期发生永久性变化，从而增加成年后患 PAH 的风险。与基因突变不同，表观遗传变化是可药物逆转的，因此作为 PAH 的治疗策略具有吸引力。本文综述了最当前的临床和表观遗传敏感变化，这些变化在早期和后期生活中都有助于 PAH 的血管重塑，重点是网络医学策略。此外，我们讨论了将基于分子网络的算法应用于 PAH 分子病理生物学的重要性，从形态发生到疾病发作。此外，我们提出了一个基于整合网络的临床疾病基因发现计划，该计划可能揭示新的生物标志物和新的疾病靶点，从而为重新定义和治疗 PAH 提供真正的创新途径，并为全面的精准医学方法治疗 PAH 提供轨迹。
