Increased Pyruvate Dehydrogenase Kinase 4 Expression in Lung Pericytes Is Associated with Reduced Endothelial-Pericyte interactions and Small Vessel Loss in Pulmonary Arterial Hypertension
Increased Pyruvate Dehydrogenase Kinase 4 Expression in Lung Pericytes Is Associated with Reduced Endothelial-Pericyte interactions and Small Vessel Loss in Pulmonary Arterial Hypertension
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DOI：
10.1016/j.ajpath.2016.05.016
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发表时间：
2016-09-01
影响因子：
6
通讯作者：
Perez, Vinicio A. de Jesus
中科院分区：
文献类型：
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作者：
Yuan, Ke;Shao, Ning-Yi;Perez, Vinicio A. de Jesus
内皮-周细胞相互作用减弱与肺动脉高压(PAH)的进行性小血管丢失有关，但这种疾病的分子机制仍然知之甚少。为了确定与周细胞异常行为相关的候选基因，我们对患者来源的供体对照和PAH肺周细胞进行了转录组分析，然后进行了功能基因组学分析。与供体对照细胞相比，PAH周细胞有大量参与各种代谢过程的基因，其中最受欢迎的是PDK4，这是一种编码一种酶的基因，这种酶抑制线粒体的活动，有利于糖酵解。鉴于有报道称线粒体活性降低与PAH细胞增殖增加有关，我们假设PDK4增加与PAH周细胞过度增殖和内皮-周细胞相互作用减少有关。我们发现，PDK4基因和蛋白在PAH周细胞中的表达显著升高，并与线粒体代谢降低、糖酵解率升高和过度增殖相关。重要的是，降低PDK4水平可以恢复线粒体新陈代谢，减少细胞增殖，并改善内皮-周细胞相互作用。据我们所知，这是第一项研究，记录了人类供体对照和PAH肺周细胞基因表达的显著差异，以及PAH中线粒体功能障碍和异常的内皮-周细胞相互作用之间的联系。这些候选基因的综合特征可以为改善内皮-周细胞相互作用和防止PAH中的小血管丢失提供新的治疗靶点。
Reduced endothelial-pericyte interactions are linked to progressive small vessel loss in pulmonary arterial hypertension (PAH), but the molecular mechanisms underlying this disease remain poorly understood. To identify relevant gene candidates associated with aberrant pericyte behavior, we performed a transcriptome analysis of patient-derived donor control and PAH lung pericytes followed by functional genomics analysis. Compared with donor control cells, PAH pericytes had significant enrichment of genes involved in various metabolic processes, the top hit being PDK4, a gene coding for an enzyme that suppresses mitochondria activity in favor of glycolysis. Given reports that link reduced mitochondria activity with increased PAH cell proliferation, we hypothesized that increased PDK4 is associated with PAH pericyte hyperproliferation and reduced endothelial-pericyte interactions. We found that PDK4 gene and protein expression was significantly elevated in PAH pericytes and correlated with reduced mitochondrial metabolism, higher rates of glycolysis, and hyperproliferation. Importantly, reducing PDK4 levels restored mitochondrial metabolism, reduced cell proliferation, and improved endothelial-pericyte interactions. To our knowledge, this is the first study that documents significant differences in gene expression between human donor control and PAH lung pericytes and the link between mitochondrial dysfunction and aberrant endothelial-pericyte interactions in PAH. Comprehensive characterization of these candidate genes could provide novel therapeutic targets to improve endothelial-pericyte interactions and prevent small vessel loss in PAH.