FGF21抗高血压的分子机制研究

Fibroblast growth factor (FGF) 21 is a novel hormone produced predominantly in the liver, with multiple biofunctions of material and energy metabolism, and closely associated with the pathogenesis of metabolic diseases. Our previous studies indicated that loss of FGF21 significantly worsens angiotensin II-induced hypertension and vascular damage in mice as evidenced by increasing blood pressure, aortic thickness, collagen accumulation and monocytes infiltration, amplifying aortic inflammatory response, promoting endothelial dysfunction and ROS production as well as smooth muscle cell proliferation. Contrast, AAV-mediated FGF21 overexpression profoundly reverses these negative effects. However, the exact molecular mechanism of FGF21 against hypertension keeps unclear. In present study, we will explore and evaluate several key issues shown as following description, by using of FGF21 null mice and cultured cells. Firstly, what is the molecular mechanism of FGF21 against angiotensin II-induced hypertension? Secondly, what role does FGF21 play in salt-induced hypertension and vascular injury? And finally, whether FGF21 presents a same protective effect and similar molecular mechanism in both angiotensin II- and salt-induced hypertension? We believe that our present study will be beneficial to clarify the molecular mechanism of FGF21 against hypertension, and provides a novel target for the development of anti-hypertensive drug.

FGF21是一种主要从肝脏细胞分泌的具有多种代谢调节功能的新型激素，直接参与机体物质能量代谢调控，与多种代谢性疾病发病密切相关。我们的前期研究表明，FGF21基因缺失加速血管紧张素II诱导的高血压病变和血管损伤，而AAV介导FGF21表达则显著抑制这些负面效应，但其具体分子机制未明。本课题旨在以FGF21基因敲除小鼠为模型，采用细胞和动物相结合的方式，深入探索下面几个问题：①FGF21是通过何种方式参与调节血管紧张素II引发的高血管病变？②FGF21在盐诱导的高血压及血管损伤扮演着何种角色？③FGF21对盐诱导高血压病变的调控机制与血管紧张素II引发高血压病变有何不同？本项目实验结果将有助于阐明以FGF21参与调节高血压病变的分子机制，为开发新型治疗高血压药物提供新靶点。

FGF21是一种主要从肝脏细胞分泌的具有多种代谢调节功能的新型激素，直接参与机体物质能量代谢调控，与多种代谢性疾病发病密切相关。我们的前期研究表明，FGF21基因缺失加速AngII诱导的高血压病变和血管损伤，而AAV介导FGF21表达则显著抑制这些负面效应，但其具体分子机制未明。.本项目结果发现：一方面，FGF21可以通过上调脂肪和肾脏组织中ACE2的表达，降低AngII的含量，并进一步促进Ang-(1-7)的生成，激活其受体MAS信号通路，从而发挥其抗AngII诱导的高血压病变。另一方面，FGF21基因缺失会加重DOCA-Salt诱导的小鼠高血压，相反，FGF21过表达会降低DOCA-Salt诱导的小鼠高血压水平。同时，我们发现，DOCA-Salt诱导的血压上升、血管损伤、肾脏损伤及水钠潴留，经罗格列酮处理后这些负面效应被明显抑制。罗格列酮可能通过间接增加血APN的含量，介导抗DOCA-Salt诱导的高血压损伤，并且这种保护作用可能是通过调节肾脏水钠潴留进行的，而APN基因缺失会加重DOCA-Salt诱导高血压导致的水钠潴留。有意思的是，APN基因缺失使FGF21的改善作用减弱甚至消失，从而加剧DOCA-Salt诱导高血压所致的病理损害。因此，APN可能介导 FGF21对DOCA-Salt诱导的高血压和血管损伤发挥保护效应。临床实验研究发现，CABG术后血清FGF21水平可能是MI患者CABG术后MACE发生率的一个很好的预测指标，测定血清FGF21水平有助于识别CABG术后MI患者MACE的高低风险。本项目阐明了FGF21参与调节AngII及DOCA-Salt诱导的高血压病变的不同分子机制，为开发新型治疗高血压药物提供了新靶点。