血管平滑肌的高磷/TGF-β1/PPARγ信号激活导致血压和心率节律异常的机制研究

In most living organisms, circadian rhythms oscillate over 24 hour periods. This strongly influences human biology and pathology, including cardiovascular disease. An endogenous timing mechanism, the circadian clock, causes rhythmic expression of a considerable fraction of the genome in most organs, including blood vessels. This optimally aligns their physiology and behavior with their environments. The cardiovascular system appears to follow such a rhythm, as heart rate and blood pressure (BP) both peak during the daytime and reach a nadir at night. .It is now accepted that hyperphosphatemia, a distinct syndrome associated with chronic kidney disease (CKD), plays vital role in abnormal cardiovascular circadian rhythms. However, the related pathogenesis is unclear. We have proved that (1) peroxisome proliferator-activated receptor-γ (PPARγ) plays an important role in vascular smooth muscle cells (VSMCs) by acting as a peripheral factor in regulation of circadian rhythms, vasoconstriction and vasorelaxation; (2) PPARγ deficiency in VSMCs causes a significant reduction of circadian variations in blood pressure and heart rate in parallel with impaired rhythmicity of the clock genes; (3) TGF-β1 pathway is activated and the expression of PPARγ is promptly inhibited in VSMCs under high-phosphate conditions. There is also obvious disruption in the circadian rhythms of VSMCs incubated in a high phosphate environment in vitro; (4) Supplemental PPARγ agonist can upregulate circadian genes in thoracic aortae in CKD mice with hyperphosphatemia. It has been reported that changes in extracellular phosphorus concentrations may directly modulate vascular function and thereby modulate the vascular smooth muscle response to physiological or pathological stimuli in normal and CKD mice. Here we hypothesize that activation of the high-phosphate/TGF-β1/PPARγ pathway in vascular smooth muscle cells induces abnormal circadian rhythm and dysregulated vasoconstriction and vasorelaxation, which in turn produce abnormal diurnal variation in blood pressure and heart rate. This project are performed in clinical investigation, animal models and in vitro experiments. Our research will highlight how circadian genes expression in VSMCs are modulated under high-phosphate conditions and how vasoconstriction and vasorelaxation are influenced from the perspective of chronobiology. The intermodulatory relationship between the TGF-β1 pathway and PPARγ will be analyzed. This project will determine the treatment value of controlling serum phosphate levels and supplemental PPARγ agonist for circadian rhythm disorders in cardiovascular systems. Our research findings will be of great help in the establishment of a novel chronotherapeutic approach to cardiovascular disorders in CKD patients.

近年昼夜节律与心血管疾病的关系研究蓬勃发展。高磷血症是慢性肾脏病（CKD）血压和心率节律异常的独立危险因素，机制尚属未知。申请人前期工作证实：血管平滑肌（VSMCs）的过氧化物酶增殖物激活受体γ（PPARγ）是维持血管生物钟和舒缩功能平衡的重要因素，直接调控血压和心率昼夜节律；高磷使VSMCs的PPARγ减少、节律基因表达异常，阻断TGF-β1通路可上调VSMCs的PPARγ水平。有报道降磷能改善CKD小鼠的血管平滑肌舒缩功能，由此我们提出假说：“血管平滑肌高磷/TGF-β1/PPARγ 通路激活使血管生物钟和昼夜舒缩功能异常，诱发血压和心率节律紊乱”。本项目将在临床研究、动物模型和体外实验中，论证高磷导致血管平滑肌节律和舒缩功能的动态变化，解析TGF-β1通路与PPARγ的互调关系，揭示降血磷和PPARγ激动剂对心血管节律紊乱的治疗意义，为探索CKD心血管并发症提供时间生物学的新思路。

近年来昼夜节律与心血管疾病的关系研究蓬勃发展。心率变异性（heart rate variability, HRV）下降是心血管节律异常的重要表现。本研究证实，慢性肾脏病-矿物质骨代谢紊乱（Chronic Kidney Disease-Mineral and Bone Disorder, CKD-MBD）与心率变异性下降密切相关，对于继发性甲状旁腺功能亢进（Secondary Hyperparathyroidism, SHPT）患者，甲状旁腺切除术（parathyroidectomy, PTX）可纠正患者异常的矿物质骨代谢紊乱，改善心率昼夜节律异常。已证实血管与心率节律调节密切相关。高磷血症是慢性肾脏病的常见并发症，本课题发现高磷环境通过抑制过氧化物酶体增殖物激活受体γ（Peroxisome proliferator-activated receptor γ, PPARγ）的生物节律引起血管平滑肌细胞（vascular smooth muscle cells, VSMCs）的节律紊乱，控制高磷血症对维持慢性肾病患者的心血管昼夜节律具有重要意义，PPARγ可能成为CKD患者心血管疾病的治疗靶点。本研究为解析CKD-MBD心血管并发症的发病机制和防治措施提供了时间生物学的新思路。