Hadjer Namous , Maria Giuseppina Strillacci , Camila Urbano Braz , Dhanu Shanmuganayagam , Christian Krueger , Athanasios Peppas , William C. Soffregen , Jess Reed , Juan F. Granada , Hasan Khatib
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引用次数: 0
Abstract
Background and aim
The complex dynamic interplay between different biological pathways involved in atherosclerosis development has rendered the identification of specific therapeutic targets a challenging quest. We aimed to identify specific genes and mechanistic pathways associated with the early development of fibro-atheromas in a swine model of atherosclerosis.
Methods
The Wisconsin Miniature Swine™ model of Familial Hypercholesterolemia (WMS-FH, n = 11) and genetically related WMS controls (WMS-N, n = 11) were used. The infrarenal aorta was harvested from both groups for histopathologic and transcriptomic profiling at 12 months. Bioinformatic analysis was performed to identify hub genes and pathways central to disease pathophysiology. The expression of ITGB2, the top ranked hub gene, was manipulated in cell culture and the expression of interconnected genes was tested.
Results
Fibro-atheromatous lesions were documented in all WMS-FH aortic tissues and displayed internal elastic lamina (IEL) disruption, significant reduction of myofibroblast presence and disorganized collagen deposition. No fibro-atheromas were observed in the control group. A total of 266 differentially expressed genes (DEGs) were upregulated in WMS-FH aortic tissues, while 29 genes were downregulated. Top identified hub genes included ITGB2, C1QA, LCP2, SPI1, CSF1R, C5AR1, CTSS, MPEG1, C1QC, and CSF2RB. Overexpression of ITGB2 resulted in elevated expression of other interconnected genes expressed in porcine endothelial cells.
Conclusion
In a swine translational model of atherosclerosis, transcriptomic analysis identified ITGB2 as a central hub gene associated inflammation and early fibroatheroma development making it a potential therapeutic target at this stage of disease.
背景与目的动脉粥样硬化发展过程中不同生物学途径之间复杂的动态相互作用使得确定特定的治疗靶点成为一项具有挑战性的任务。我们的目的是在猪动脉粥样硬化模型中确定与纤维动脉粥样硬化早期发展相关的特定基因和机制途径。方法采用威斯康辛小型猪™家族性高胆固醇血症模型(WMS- fh, n = 11)和遗传相关的WMS对照组(WMS- n, n = 11)。12个月时采集两组的肾下主动脉进行组织病理学和转录组学分析。进行生物信息学分析以确定疾病病理生理的中心基因和通路。在细胞培养中操纵排在首位的枢纽基因ITGB2的表达,并检测互联基因的表达。结果所有WMS-FH主动脉组织均出现纤维粥样硬化病变,并表现为内部弹性层(IEL)破坏,肌成纤维细胞存在明显减少,胶原沉积紊乱。对照组未见纤维动脉粥样硬化。在WMS-FH主动脉组织中,共有266个差异表达基因(DEGs)上调,29个基因下调。最高鉴定的枢纽基因包括ITGB2、C1QA、LCP2、SPI1、CSF1R、C5AR1、CTSS、MPEG1、C1QC和CSF2RB。ITGB2的过表达导致猪内皮细胞中其他相关基因的表达升高。在猪动脉粥样硬化的翻译模型中,转录组学分析发现ITGB2是炎症和早期纤维动脉粥样硬化发展相关的中心枢纽基因,使其成为该疾病阶段的潜在治疗靶点。