Wasiak Sylwia, Tsujikawa Laura M, Daze Emily, Gilham Dean, Stotz Stephanie C, Rakai Brooke D, Sarsons Chris D, Fu Li, Azhar Salman, Jahagirdar Ravi, Sweeney Michael, Johansson Jan O, Wong Norman C W, Kulikowski Ewelina
Resverlogix Corp., 300-4820 Richard Road SW, Calgary, AB, T3E 6L1, Canada.
VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA, 94304, USA.
Atherosclerosis. 2023 Jan;364:10-19. doi: 10.1016/j.atherosclerosis.2022.11.015. Epub 2022 Nov 23.
Obese patients are at risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). A lipid-rich diet promotes arterial changes by inducing hypertension, oxidative stress, and inflammation. Bromodomain and extraterminal (BET) proteins contribute to endothelial and immune cell activation in vitro and in atherosclerosis mouse models. We aim to determine if BET inhibition can reduce lipid-rich diet-induced vascular inflammation in mice.
Body weight, serum glucose and lipid levels were measured in mice fed a high-fat diet (HFD) or low-fat diet (LFD) for 6 weeks and at study termination. BET inhibitors apabetalone and JQ1 were co-administered with the HFD for additional 16 weeks. Aortic gene expression was analyzed post necropsy by PCR, Nanostring nCounter® Inflammation Panel and bioinformatics pathway analysis. Transcription changes and BRD4 chromatin occupancy were analyzed in primary human endothelial cells in response to TNFα and apabetalone.
HFD induced weight gain, visceral obesity, high fasting blood glucose, glucose intolerance and insulin resistance compared to LFD controls. HFD upregulated the aortic expression of 47 genes involved in inflammation, innate immunity, cytoskeleton and complement pathways. Apabetalone and JQ1 treatment reduced HFD-induced aortic expression of proinflammatory genes. Congruently, bioinformatics predicted enhanced signaling by TNFα in the HFD versus LFD aorta, which was countered by BETi treatment. TNFα-stimulated human endothelial cells had increased expression of HFD-sensitive genes and higher BRD4 chromatin occupancy, which was countered by apabetalone treatment.
HFD induces vascular inflammation in mice through TNFα signaling. Apabetalone treatment reduces this proinflammatory phenotype, providing mechanistic insight into how BET inhibitors may reduce CVD risk in obese patients.
肥胖患者有患2型糖尿病（T2DM）和心血管疾病（CVD）的风险。富含脂质的饮食通过诱发高血压、氧化应激和炎症促进动脉病变。溴结构域和额外末端（BET）蛋白在体外及动脉粥样硬化小鼠模型中可促进内皮细胞和免疫细胞活化。我们旨在确定抑制BET是否能减轻富含脂质饮食诱导的小鼠血管炎症。
给小鼠喂食高脂饮食（HFD）或低脂饮食（LFD）6周，并在研究结束时测量体重、血清葡萄糖和脂质水平。BET抑制剂阿帕贝酮和JQ1与HFD共同给药额外16周。尸检后通过聚合酶链反应（PCR）、Nanostring nCounter®炎症检测板和生物信息学通路分析来分析主动脉基因表达。分析原代人内皮细胞对肿瘤坏死因子α（TNFα）和阿帕贝酮反应时的转录变化及BRD4染色质占据情况。
与LFD对照组相比，HFD导致体重增加、内脏肥胖、高空腹血糖、葡萄糖不耐受和胰岛素抵抗。HFD上调了主动脉中47个参与炎症、固有免疫、细胞骨架和补体通路的基因的表达。阿帕贝酮和JQ1治疗降低了HFD诱导的主动脉促炎基因表达。同样，生物信息学预测HFD组主动脉中TNFα信号增强，而BETi治疗可对抗这种增强。TNFα刺激的人内皮细胞中HFD敏感基因的表达增加且BRD4染色质占据更高，而阿帕贝酮治疗可对抗这种情况。
HFD通过TNFα信号传导诱导小鼠血管炎症。阿帕贝酮治疗可减轻这种促炎表型，为BET抑制剂如何降低肥胖患者CVD风险提供了机制性见解。
