背景:作为基因表达的关键调节因子,microRNAs影响许多心血管机制,并与几种心血管疾病有关。在这项研究中,我们的目的是研究全血microRNAs与血管功能的几个定量测量的关系,并通过整合microRNA-基因表达分析探讨其生物学作用。
方法:通过RNA-Seq对2606名参与者(45.8%男性,平均年龄:53.93岁,年龄范围:30至95岁)来自莱茵兰研究,波恩正在进行的基于人群的队列研究,德国。使用加权基因共表达网络分析将具有高度相关表达水平的microRNA聚类为14个模块。通过线性回归模型,我们调查了每个模块的表达与血管健康的定量标志物之间的关联,包括脉搏波速度,总动脉顺应性指数,心脏指数,中风指数,全身血管阻力指数,反应性皮肤充血和白质高强度负荷。对于与至少一个特征关联的每个模块,定义了一个或多个驱动关联的hub-microRNA.通过定位到推定的靶基因,随后进行基因本体论途径分析,进一步表征了Hub-microRNA。
结果:四个模块,由hub-microRNAsmiR-320家族代表,miR-378家族,miR-3605-3p,miR-6747-3p,miR-6786-3p,还有miR-330-5p,与总动脉顺应性指数相关。重要的是,miR-320家族模块也与白质高强度负荷相关,部分通过动脉顺应性介导的作用。此外,hub-microRNAmiR-192-5p与心脏指数相关。功能分析证实了所鉴定的microRNAs与血管功能的相关性,其中,富集参与血管形态发生和发育的途径,血管生成,端粒的组织和维护,和胰岛素分泌。
结论:我们鉴定了几种与心血管功能密切相关的微小RNA,尤其是动脉顺应性和心输出量.此外,我们的结果强调miR-320是脑血管损伤的调节因子,部分通过调节血管功能。由于许多这些microRNAs参与与血管发育和衰老相关的生物过程,我们的研究结果有助于对血管生理学的理解,并为心血管疾病的预防提供了可能的目标.
BACKGROUND: As key regulators of gene expression, microRNAs affect many cardiovascular mechanisms and have been associated with several cardiovascular diseases. In this
study, we aimed to investigate the relation of whole blood microRNAs with several quantitative measurements of vascular function, and explore their biological role through an integrative microRNA-gene expression analysis.
METHODS: Peripheral whole blood microRNA expression was assessed through RNA-Seq in 2606 participants (45.8% men, mean age: 53.93, age range: 30 to 95 years) from the Rhineland
Study, an ongoing population-based cohort
study in Bonn, Germany. Weighted gene co-expression network analysis was used to cluster microRNAs with highly correlated expression levels into 14 modules. Through linear regression models, we investigated the association between each module\'s expression and quantitative markers of vascular health, including pulse wave velocity, total arterial compliance index, cardiac index, stroke index, systemic vascular resistance index, reactive skin hyperemia and white matter hyperintensity burden. For each module associated with at least one trait, one or more hub-microRNAs driving the association were defined. Hub-microRNAs were further characterized through mapping to putative target genes followed by gene ontology pathway analysis.
RESULTS: Four modules, represented by hub-microRNAs miR-320 family, miR-378 family, miR-3605-3p, miR-6747-3p, miR-6786-3p, and miR-330-5p, were associated with total arterial compliance index. Importantly, the miR-320 family module was also associated with white matter hyperintensity burden, an effect partially mediated through arterial compliance. Furthermore, hub-microRNA miR-192-5p was related to cardiac index. Functional analysis corroborated the relevance of the identified microRNAs for vascular function by revealing, among others, enrichment for pathways involved in blood vessel morphogenesis and development, angiogenesis, telomere organization and maintenance, and insulin secretion.
CONCLUSIONS: We identified several microRNAs robustly associated with cardiovascular function, especially arterial compliance and cardiac output. Moreover, our results highlight miR-320 as a regulator of cerebrovascular damage, partly through modulation of vascular function. As many of these microRNAs were involved in biological processes related to vasculature development and aging, our results contribute to the understanding of vascular physiology and provide putative targets for cardiovascular disease prevention.