Benincasa Giuditta, Coscioni Enrico, Napoli Claudio
Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", Pz. Miraglia 2, Naples 80138, Italy.
Division of Cardiac Surgery, AOU San Giovanni di Dio e Ruggid'Aragona, 84131 Salerno, Italy.
Biochem Pharmacol. 2022 Aug;202:115108. doi: 10.1016/j.bcp.2022.115108. Epub 2022 May 26.
One of the major challenges of cardiovascular primary prevention approach is the absence of early biomarkers of endothelial dysfunction which may be useful for identifying at-risk subjects. Endothelial dysfunction is a systemic disorder in which traditional cardiovascular risk factors, such as aging, gender, hypertension, smoking, hyperglycemia, and dyslipidemia, as well as emerging risk determinants, such as fetal factors, gut microbiome alteration, clonal hematopoiesis, air pollution, and sleep disorders act synergistically to tip the endothelial balance in favor of vasoconstrictive, pro-inflammatory, and pro-thrombotic phenotypes. Endothelial dysfunction can start already in fetal life and may be regained once detrimental stimuli are removed. The hallmark of endothelial dysfunction is a marked reduction of nitric oxide (NO) bioavailability owing to epigenetic-sensitive dysregulation of the endothelial nitric oxide synthase (eNOS) gene and upregulation of reactive oxygen species (ROS) in endothelial cells (ECs). Advance in liquid-based assays and molecular biology tools are providing novel potential EC-specific biomarkers for prediction and diagnosis of endothelial dysfunction. Significant associations between clinically useful indexes of endothelial dysfunction, mainly brachial artery flow-mediated dilation (FMD), and increased number of endothelial microparticles (EMPs), increased levels of endoglin and endocan, as well as reduced levels of irisin were observed in subjects with one or more traditional risk factors. However, none entered in clinical practice yet. Smoking cessation, weight loss, physical exercise, and diet control are the milestones of cardiovascular primary prevention, and they may restore endothelial function via epigenetic-sensitive pathways able to reduce inflammation and oxidative stress and increase NO production . We briefly summarize well-known and novel molecular routes driving early endothelial dysfunction mainly in human ECs and related potential biomarkers which may add predictive or diagnostic value to the traditional non-invasive techniques. Also, we focus on clinical trials investigating lifestyle modifications and their impact on molecular routes involved in restoring endothelial function.
心血管一级预防方法的主要挑战之一是缺乏内皮功能障碍的早期生物标志物，而这些标志物可能有助于识别高危人群。内皮功能障碍是一种全身性疾病，在这种疾病中，传统的心血管危险因素，如衰老、性别、高血压、吸烟、高血糖和血脂异常，以及新出现的风险决定因素，如胎儿因素、肠道微生物群改变、克隆性造血、空气污染和睡眠障碍，会协同作用，使内皮平衡倾向于血管收缩、促炎和促血栓形成表型。内皮功能障碍在胎儿期就可能开始，一旦有害刺激被消除，可能会恢复。内皮功能障碍的标志是由于内皮型一氧化氮合酶（eNOS）基因的表观遗传敏感性失调和内皮细胞（ECs）中活性氧（ROS）的上调，一氧化氮（NO）生物利用度显著降低。基于液体的检测方法和分子生物学工具的进展正在为内皮功能障碍的预测和诊断提供新的潜在的内皮细胞特异性生物标志物。在有一个或多个传统危险因素的受试者中，观察到内皮功能障碍的临床有用指标（主要是肱动脉血流介导的舒张功能（FMD））与内皮微粒（EMPs）数量增加、内皮糖蛋白和内皮抑素水平升高以及鸢尾素水平降低之间存在显著关联。然而，尚无一种进入临床实践。戒烟、减肥、体育锻炼和饮食控制是心血管一级预防的里程碑，它们可能通过能够减少炎症和氧化应激并增加NO生成的表观遗传敏感途径来恢复内皮功能。我们简要总结了主要在人类内皮细胞中导致早期内皮功能障碍的已知和新的分子途径以及相关的潜在生物标志物，这些生物标志物可能为传统的非侵入性技术增加预测或诊断价值。此外，我们关注研究生活方式改变及其对参与恢复内皮功能的分子途径影响的临床试验。
