Cong Guangzhi, Cui Xiangdong, Ferrari Ricardo, Pipinos Iraklis I, Casale George P, Chattopadhyay Ansuman, Sachdev Ulka
Department of Surgery, University of Pittsburgh Medical Centre, Pittsburgh, PA 15217, USA.
Department of Surgery, University of Nebraska at Medical Center, Omaha, NE 68198, USA.
J Clin Med. 2020 Dec 8;9(12):3974. doi: 10.3390/jcm9123974.
Most patients with critical limb ischemia (CLI) from peripheral arterial disease (PAD) do not have antecedent intermittent claudication (IC). We hypothesized that transcriptomic analysis would identify CLI-specific pathways, particularly in regards to fibrosis. Derivation cohort data from muscle biopsies in PAD and non-PAD (controls) was obtained from the Gene Expression Omnibus (GSE120642). Transcriptomic analysis indicated CLI patients (N = 16) had a unique gene expression profile, when compared with non-PAD controls (N = 15) and IC (N = 20). Ninety-eight genes differed between controls and IC, 2489 genes differed between CLI and controls, and 2783 genes differed between CLI and IC patients. Pathway enrichment analysis showed that pathways associated with TGFβ, collagen deposition, and VEGF signaling were enriched in CLI but not IC. Receiver operating curve (ROC) analysis of nine fibrosis core gene expression revealed the areas under the ROC (AUC) were all >0.75 for CLI. Furthermore, the fibrosis area (AUC = 0.81) and % fibrosis (AUC = 0.87) in validation cohort validated the fibrosis discrimination CLI from IC and control (all n = 12). In conclusion, transcriptomic analysis identified fibrosis pathways, including those involving TGFβ, as a novel gene expression feature for CLI but not IC. Fibrosis is an important characteristic of CLI, which we confirmed histologically, and may be a target for novel therapies in PAD.
大多数因外周动脉疾病（PAD）导致严重肢体缺血（CLI）的患者并无先前的间歇性跛行（IC）。我们推测转录组分析能够识别出CLI特异性通路，尤其是在纤维化方面。来自PAD患者和非PAD患者（对照组）肌肉活检的衍生队列数据取自基因表达综合数据库（GSE120642）。转录组分析表明，与非PAD对照组（N = 15）和IC患者（N = 20）相比，CLI患者（N = 16）具有独特的基因表达谱。对照组与IC患者之间有98个基因存在差异，CLI患者与对照组之间有2489个基因存在差异，CLI患者与IC患者之间有2783个基因存在差异。通路富集分析显示，与TGFβ、胶原蛋白沉积和VEGF信号传导相关的通路在CLI患者中富集，但在IC患者中未富集。对9个纤维化核心基因表达进行的受试者工作特征曲线（ROC）分析显示，CLI患者的ROC曲线下面积（AUC）均>0.75。此外，验证队列中的纤维化面积（AUC = 0.81）和纤维化百分比（AUC = 0.87）验证了CLI与IC及对照组在纤维化鉴别方面的差异（所有n = 12）。总之，转录组分析确定了纤维化通路，包括涉及TGFβ的通路，作为CLI而非IC的一种新的基因表达特征。纤维化是CLI的一个重要特征，我们通过组织学证实了这一点，并且它可能是PAD新型治疗的一个靶点。
