动脉硬化是高血压亚临床靶器官损害表现之一，是心脑血管疾病的重要预测标志。但动脉硬化的发病机理仍不清楚，缺乏针对性的干预手段。血管平滑肌细胞骨化及胶原沉积是动脉硬化的关键机制之一。我们前期自然基金课题研究结果显示，FGF23/Klotho参与了高磷引起的血管钙化，Klotho蛋白表达减少可能是血管硬化的一个关键环节。本课题将在此基础上，利用已建立的高血压患者研究队列，前瞻性地分析FGF23/Klotho基因变异及其血清蛋白水平与动脉硬化进展的关系。在细胞水平，利用慢病毒转染技术，明确Klotho蛋白表达减少在血管平滑肌细胞骨化形成及胶原沉积中的作用，探讨其可能的细胞内转导途径如PTEN/AKT/FOXO、WNT/β-catenin通路；以及以Klotho蛋白及作用途径作为干预靶点，绿茶多酚EGCG对其的调节功能及对血管硬化的作用。

Arterial stiffness is one of the subclinical target organ damage phenotypes of hypertension, and is an important prognostic marker of cardiovascular diseases. However, the mechanisms of arterial stiffness remain unclear and specific intervention therapy was still lacking. Osteogenesis of vascular smooth muscle cells and collagen deposition is one of the important causes of arterial stiffness. Our previous NSFC project showed that FGF23/Klotho system was involved in the high phosphate-induced vascular calcification and the deficiency of Klotho expression might play a key role in arterial stiffness. Based on these results, we will further study the relationship of arterial stiffness progression with serum FGF23/Klotho and their genetic variants using our established prospective hypertensive patient cohort. At the cellular experiments, with the use of lentiviral transfection, we will explore if Klotho deficiency will result in osteogenesis of vascular smooth muscle cells and collagen deposition, and study the possible intracellular pathways of PTEN/AKT/FOXO、WNT/β-catenin of Klotho deficiency, and investigate if EGCG, one of the green tea polyphenols, could improve arterial stiffness via targeting the Klotho deficiency.