Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension.
Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension.
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DOI：
10.1172/jci161077
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发表时间：
2022-05-16
影响因子：
15.9
通讯作者：
Chan, Stephen Y.
中科院分区：
文献类型：
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作者：
Bertero, Thomas;Lu, Yu;Annis, Sofia;Hale, Andrew;Bhat, Balkrishen;Saggar, Rajan;Saggar, Rajeev;Wallace, W. Dean;Ross, David J.;Vargas, Sara O.;Graham, Brian B.;Kumar, Rahul;Black, Stephen M.;Fratz, Sohrab;Fineman, Jeffrey R.;West, James D.;Haley, Kathleen J.;Waxman, Aaron B.;Chau, B. Nelson;Cottrill, Katherine A.;Chan, Stephen Y.
肺动脉高压（PH）是一种神秘的血管疾病，其分子起源尚不清楚。它由各种不同的触发因素（缺氧和炎症等）驱动;其特征在于复杂分子途径的病理性失衡，进而促进许多细胞病理表型（如增殖和血管收缩）;并且它影响多种血管细胞类型，包括肺动脉内皮细胞（PAEC）和平滑肌细胞（PASMC）。协调整合这些庞大的分子程序的调节因子的鉴定将不仅提供对PH的分子发生的基本见解，而且还将大大改善上游疾病起源的治疗靶向策略。然而，PH的复杂性使得难以通过标准的还原主义实验策略来识别这些因素。鉴于其固有的多效性作用，同时抑制多个基因靶点，microRNAs（miRNAs）可能是理想的候选人，以提供全面和综合的控制PH发病机制。在心脏组织（1）和癌症（2）中已经开始描述上游"主miRNA"对从属miRNA的高阶调节，并且可能是某些基于miRNA的健康和疾病作用的稳健性的基础。已经提出了计算方法来破译涉及miRNA的系统水平调控基序（3，4），但这些理论在实验研究中具有挑战性（如参考文献5所述）。因此，这些理论在体内人类疾病中的前瞻性验证还有待探索。事实上，迄今为止，先前与PH相关的miRNA主要与离散的细胞特异性机制和表型相关（6）。例如，在患病的PASMC中，STAT3下调平滑肌特异性miR-204并通过激活SRC激酶增加细胞增殖（7）。或者，在患病的PAEC中，apelin（APLN）的下调减少了miR-424/503，从而通过增加的FGF2增加增殖（8）。传统的分子实验已经不足以辨别这些途径的更全面，更高阶的调节，以及这些和其他基于miRNA的机制是否被协调控制以更有力地影响PH表现。在此之前，我们设计了一种基于网络的生物信息学方法（9）来预测控制PH发病机制的计算机miRNA-通过对miRNA的排序，通过公认的识别多种血管疾病肺动脉高压（PH）的发展涉及跨越多种细胞类型的不同分子途径。微小RNA（miRNAs）可能协同调节PH进展，但miRNAs在此过程中的整合功能一直难以用常规方法定义。在这里，对PH特异性分子网络结构的分析预测，miR-130/301家族是PH中细胞增殖的主要调节因子，其通过调节彼此之间具有意想不到的连接的从属miRNA途径来实现。在该模型的验证中，来自哺乳动物模型和人类PH受试者的患病肺血管和血浆表现出miR-130/301表达的上调。对肺动脉内皮细胞和平滑肌细胞的评估显示，miR-130/301靶向的PPAR γ具有不同的结果。在内皮细胞中，miR-130/301调节apelin-miR-424/503-FGF2信号传导，而在平滑肌细胞中，miR-130/301调节STAT3-miR-204信号传导以促进PH相关表型。在小鼠模型中，miR-130/301的诱导促进了...
Pulmonary hypertension (PH) is an enigmatic vascular disease with poorly defined molecular origins. It is driven by various disparate triggers (hypoxia and inflammation, among others); it is marked by a pathologic imbalance of complex molecular pathways in turn promoting a number of cellular pathophenotypes (such as proliferation and vasoconstriction); and it affects multiple vascular cell types, including pulmonary arterial endothelial cells (PAECs) and smooth muscle cells (PASMCs). Identification of a regulatory factor (s) that coordinately integrates these vast molecular programs would not only offer fundamental insight into the molecular genesis of PH but also would greatly improve the strategies for therapeutic targeting of the upstream disease origins. However, the complexity of PH has made difficult the identification of such factors by standard reductionist strategies of experimentation. Given their inherent pleiotropic actions to repress multiple gene targets simultaneously, microRNAs (miRNAs) may be ideal candidates to provide comprehensive and integrated control of PH pathogenesis. Higher-order regulation of subordinate miRNAs by upstream “master miRNAs” has begun to be described in cardiac tissue (1) and cancer (2) and may underlie the robustness of certain miRNA-based actions in health and disease. Computational approaches have been proposed to decipher systems-level regulatory motifs involving miRNAs (3, 4), but these theories have been challenging to study experimentally (as reviewed by ref. 5). Thus, the prospective validation of these theories in human disease in vivo has yet to be explored. In fact, to date, the miRNAs previously linked to PH have been associated primarily with discrete cell-specific mechanisms and phenotypes (6). For example, in diseased PASMCs, STAT3 downregulates the smooth muscle-specific miR-204 and increases cellular proliferation via activating SRC kinase (7). Alternatively, in diseased PAECs, downregulation of apelin (APLN) reduces miR-424/503, thus increasing proliferation via increased FGF2 (8). Conventional molecular experimentation alone has been inadequate to discern more comprehensive, higher-order regulation of these pathways and whether these and other miRNA-based mechanisms are coordinately controlled to affect PH manifestation more robustly. Previously, we designed a network-based bioinformatics approach (9) to predict in silico miRNAs controlling PH pathogenesis—via ranking of miRNAs by putative ability to recognize multipleDevelopment of the vascular disease pulmonary hypertension (PH) involves disparate molecular pathways that span multiple cell types. MicroRNAs (miRNAs) may coordinately regulate PH progression, but the integrative functions of miRNAs in this process have been challenging to define with conventional approaches. Here, analysis of the molecular network architecture specific to PH predicted that the miR-130/301 family is a master regulator of cellular proliferation in PH via regulation of subordinate miRNA pathways with unexpected connections to one another. In validation of this model, diseased pulmonary vessels and plasma from mammalian models and human PH subjects exhibited upregulation of miR-130/301 expression. Evaluation of pulmonary arterial endothelial cells and smooth muscle cells revealed that miR-130/301 targeted PPARγ with distinct consequences. In endothelial cells, miR-130/301 modulated apelin-miR-424/503-FGF2 signaling, while in smooth muscle cells, miR-130/301 modulated STAT3-miR-204 signaling to promote PH-associated phenotypes. In murine models, induction of miR-130/301 promoted …