FGF21改善动脉粥样硬化病变小鼠血管功能的潜在机制研究

Fibroblast growth factor (FGF21) is a type of novel hormone secreted mainly from hepatocytes with many beneficial metabolism regulatory functions including attenuating hypertension, improving lipid dysfunction, inhibiting obesity and fatty liver disease. Other and our recent human-based studies demonstrated that circulating FGF21 levels are significantly increased in patients with atherosclerosis, and markedly associated with carotid atherosclerosis independent of established cardiovascular risk factors. However, the exact role and relevant mechanism of FGF21 in atherosclerosis remain unclear. To explore the relationship between FGF21 and the onset and development of atherosclerosis, we built up FGF21 and apolipoprotein E double knockout (FGF21. apoE DKO) mice, and our primary results demonstrated that FGF21 deficiency accelerated atherosclerosis development. In this study, we will explore and answer next several questions made use of the J FGF21. apoE DKO mice: (1) whether FGF21 deficiency will affect the vascular systolic and diastolic function in apolipoprotein E knockout (apoE KO)mice? (2) To explore the impact of relevant factors that involve in the communication between vascular and perivascular adipose tissue in FGF21 deficient apoE KO mice. (3) To observe the different distribution of M1/M2 of mononuclear macrophage and the difference of foam cells developed from macrophage between FGF21.apoE DKO and apoE KO mice. (4) To clarify the change of apolipoprotein metabolism between FGF21.apoE DKO and apoE KO mice. Our study will help to clarify the role of FGF21 during the onset and development of atherosclerosis, and the exact mechanism of FGF21 improving vascular function and maintaining steady state of vascular and against atherosclerosis.

FGF21是一种具有降低血糖、改善异常血脂、胰岛素增敏等多种生物功能的新型激素。我们的前期研究发现，FGF21循环水平在动脉粥样硬化(AS)患者中显著升高，并与颈动脉内膜厚度及其它AS发病危险因子高度相关，但其具体的角色及分子机制未明。为了探索FGF21与AS发病之间的关系，我们构建了FGF21.apoE 双基因敲除(DKO)小鼠，并初步观察到FGF21基因缺失加速AS斑块的发生发展。本课题通过动物与细胞相结合的方式：（1）探索FGF21对AS小鼠（apoE KO）血管收缩和舒张功能的影响；（2）观察FGF21基因缺失对维护血管稳态的血管外周脂肪组织与动脉血管壁之间交流相关因子的影响；（3）探索FGF21对单核巨噬细胞M1/M2的分布及泡沫细胞形成的影响；（4）探索FGF21对AS小鼠载脂蛋白代谢的影响。本项目的完成将有助于进一步阐明FGF21改善动脉粥样硬化病变血管功能的分子作用机制。

FGF21是一种具有降低血糖、改善异常血脂、胰岛素增敏等多种生物功能的新型激素。我们的前期研究发现，FGF21循环水平在动脉粥样硬化(AS)患者中显著升高，并与颈动脉内膜厚度及其它AS发病危险因子高度相关，但其具体的角色及潜在的分子机制未明。为了探索FGF21与AS发病之间的关系，我们构建了FGF21. apoE双基因敲除（DKO）小鼠，并采用动物与细胞相结合的研究方式：（1）观察FGF21基因缺失对AS小鼠（apoE-/-）动脉粥样硬化斑块形成的影响；（2）探索DKO小鼠对高血脂和炎症的影响；（3）探索FGF21与脂联素的相互作用及对动脉粥样硬化的影响；（4）探索FGF21对胆固醇的生物合成的影响及相关机制。我们得研究结果显示：FGF21在动脉粥样硬化小鼠病变过程中显著上调，而FGF21基因缺失导致apoE-/-小鼠动脉粥状硬化斑块显著增加，伴有严重的高胆固醇血症及低脂联素血症，增加早期的死亡率。当apoE-/-小鼠给予FGF21蛋白处理后，脂肪细胞表达分泌的脂联素水平显著上升，进而抑制血管内膜增生及巨噬细胞炎症。此外，FGF21还通过抑制肝脏SREBP-2表达、抑制胆固醇的合成、进而缓解高胆固醇血症，最终发挥其抗动脉粥样硬化的效应。. 另外，我们还研究了FGF21在糖尿病心肌病方面的作用及可能存在机制。结果发现，FGF21基因缺失加速STZ/HFD诱导的糖尿病心肌病，AAV介导FGF21表达通过减弱心脏肥大，纤维化，氧化应激和小鼠心脏炎症缓解了STZ/HFD诱导的糖尿病心肌病，FGF21通过激活AMPK信号传导途径缓解HG诱导的氧化应激和纤维化，以及FGF21通过激活心肌细胞中AMPK所依赖的PON1信号来缓解HG诱导的细胞毒性。. 以上研究结果提示，FGF21作为一种新型具有调节机体脂糖代谢、胰岛素增敏等多种生物学功效的细胞因子，在动脉粥样硬化及糖尿病心肌病病变过程中扮演着重要的角色，这些为开发具有多器官调节功能的新型抗动脉粥样硬化药及抗糖尿病心肌病药物提供了新的靶点和实验理论基础。