Translating MicroRNA Biology in Pulmonary Hypertension It Will Take More Than "miR" Words
Translating MicroRNA Biology in Pulmonary Hypertension It Will Take More Than "miR" Words
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DOI：
10.1164/rccm.201604-0886pp
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发表时间：
2017-01-15
影响因子：
24.7
通讯作者：
Chan, Stephen Y.
中科院分区：
文献类型：
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作者：
Chun, Hyung J.;Bonnet, Sebastien;Chan, Stephen Y.
肺动脉高压（PH）是一种复杂的肺血管疾病，全球患病率不断增加，特别严重的形式，如肺动脉高压（PAH），往往是致命的。在PAH中，病变肺动脉的重塑增加了右心室的血流动力学负担，导致右心室衰竭、多器官功能障碍和死亡。目前的PH药物主要针对三个主要的血管舒张途径（一氧化氮，内皮素和前列环素信号），但不针对PH的难以捉摸的上游分子起源。因此，它们既不能预防也不能逆转疾病。因此，非常需要确定疾病的上游分子触发因素，并将这些发现应用于临床益处。然而，PH的发病机制是复杂和多因素的。它涉及多种血管和非血管细胞类型，并取决于疾病表现和进展的几种致病事件（即遗传易感性，缺氧，炎症，病毒感染，DNA损伤和剪切应力等）（1，2）。由于无法完全解开这些分子复杂性，因此在开发针对该疾病的新诊断和治疗方法方面面临多重临床挑战。研究发现，microRNA（miRNAs）的失调是形成PH发展和进展的不可或缺的事件（3）。miRNA是小的非编码RNA分子，其负调节基因表达，并在动物和植物界的生物学的各个方面执行普遍的调节功能（4）。许多重要的报道已经暗示了miRNA在广泛的肺血管过程中的作用，涵盖肺血管发育、生理学和疾病，并导致对其在临床诊断和预后中的有用性的推测。然而，我们仍然处于这个不断发展的研究领域的开端，在将这种生物学应用于临床实践方面仍然存在许多挑战。在这篇综述中，我们讨论了PH中miRNA的基本生物学及其作为新型生物标志物和直接治疗方法的翻译潜力和发展障碍。
Pulmonary hypertension (PH) is a complex pulmonary vascular condition with increasing global prevalence and with particularly severe forms, such as pulmonary arterial hypertension (PAH), that are often fatal. In PAH, remodeling in diseased pulmonary arteries places an increasing hemodynamic burden on the right ventricle, leading to right ventricular failure, multiorgan dysfunction, and death. Current PH medications primarily target three major vasodilatory pathways (nitric oxide, endothelin, and prostacyclin signaling) but do not target the elusive upstream molecular origins of PH. Thus, they neither prevent nor reverse disease. Hence, there is a great need to identify the upstream molecular triggers of disease and apply those discoveries to clinical benefit. However, the pathogenesis of PH is complex and multifactorial. It involves both multiple vascular and nonvascular cell types and depends on several pathogenic events (ie, genetic susceptibility, hypoxia, inflammation, viral infection, DNA damage, and shear stress, among others) for disease manifestation and progression (1, 2). An inability to fully unravel these molecular complexities has led to multiple clinical challenges in developing both new diagnostics and therapeutics for this disease.Discoveries have identified the dysregulation of microRNAs (miRNAs) as integral events that shape the development and progression of PH (3). miRNAs are small noncoding RNA molecules that negatively regulate gene expression and perform pervasive regulatory functions in all aspects of biology, both in the animal and plant kingdoms (4). A number of key reports have implicated miRNAs in a wide range of pulmonary vascular processes, spanning pulmonary vascular development, physiology, and disease and leading to speculation on their usefulness in clinical diagnosis and prognosis. Yet, we still are at the inception of this growing field of study, and a number of challenges remain in applying this biology to clinical practice. In this review, we discuss both the fundamental biology of miRNAs in PH and the translational potential and obstacles in their development as novel biomarkers and direct therapeutics.