Pei Jiayi, Harakalova Magdalena, den Ruijter Hester, Pasterkamp Gerard, Duncker Dirk J, Verhaar Marianne C, Asselbergs Folkert W, Cheng Caroline
Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, The Netherlands.
Department of Cardiology, University Medical Center Utrecht, The Netherlands; Netherlands Heart Institute, Utrecht, The Netherlands.
Int J Cardiol. 2017 Jul 1;238:22-30. doi: 10.1016/j.ijcard.2017.03.050. Epub 2017 Mar 14.
Female gender, post-menopause, chronic kidney disease (CKD) and (CKD linked) microvascular disease are important risk factors for developing heart failure with preserved ejection fraction (HFpEF). Enhancing our understanding of the interrelation between these risk factors could greatly benefit the identification of new drug targets for future therapy. This review discusses the evidence for the protective role of estradiol (E) in CKD-associated microvascular disease and related HFpEF. Elevated circulating levels of uremic toxins (UTs) during CKD may act in synergy with hormonal changes during post-menopause and could lead to coronary microvascular endothelial dysfunction in HFpEF. To elucidate the molecular mechanism involved, published transcriptome datasets of indoxyl sulfate (IS), high inorganic phosphate (HP) or E treated human derived endothelial cells from the NCBI Gene Expression Omnibus database were analyzed. In total, 36 genes overlapped in both IS- and HP-activated gene sets, 188 genes were increased by UTs (HP and/or IS) and decreased by E, and 572 genes were decreased by UTs and increased by E. Based on a comprehensive in silico analysis and literature studies of collected gene sets, we conclude that CKD-accumulated UTs could negatively impact renal and cardiac endothelial homeostasis by triggering extensive inflammatory responses and initiating dysregulation of angiogenesis. E may protect (myo)endothelium by inhibiting UTs-induced inflammation and ameliorating UTs-related uremic bleeding and thrombotic diathesis via restored coagulation capacity and hemostasis in injured vessels.
女性、绝经后、慢性肾脏病（CKD）以及（与CKD相关的）微血管疾病是射血分数保留的心力衰竭（HFpEF）发生的重要危险因素。增进我们对这些危险因素之间相互关系的理解，可能会极大地有助于确定未来治疗的新药靶点。本综述讨论了雌二醇（E）在CKD相关微血管疾病及相关HFpEF中保护作用的证据。CKD期间循环中尿毒症毒素（UTs）水平升高可能与绝经后激素变化协同作用，并可能导致HFpEF中的冠状动脉微血管内皮功能障碍。为阐明其中涉及的分子机制，分析了来自NCBI基因表达综合数据库的经吲哚硫酸酯（IS）、高无机磷酸盐（HP）或E处理的人源内皮细胞的已发表转录组数据集。总共，36个基因在IS和HP激活的基因集中重叠，188个基因被UTs（HP和/或IS）上调而被E下调，572个基因被UTs下调而被E上调。基于对收集的基因集进行的全面计算机分析和文献研究，我们得出结论，CKD累积的UTs可能通过引发广泛的炎症反应和启动血管生成失调，对肾脏和心脏内皮稳态产生负面影响。E可能通过抑制UTs诱导的炎症，并通过恢复受损血管的凝血能力和止血来改善UTs相关的尿毒症出血和血栓形成素质，从而保护（肌）内皮。
