Nesfatin-1介导的血管平滑肌细胞表型转换在高血压血管重构中的作用研究

Vascular remodeling plays an important role in hypertension and its complications, and phenotypic switch of vascular smooth muscle cells (VSMCs) is an initiating factor for development of hypertension and vascular remodeling. The molecular mechanism of VSMC phenotype transformation is a key problem that calls for immediate solution. We have identified that the nesfatin-1 levels in plasma and the media of artery are increased in spontaneously hypertensive rats. In vitro experiments showed that nesfatin-1 could promote the phenotype transformation of VSMCs, suggesting that nesfatin-1 may be important for phenotypic transformation of VSMCs and vascular remodeling in hypertension. Based on the crucial finding, the project will be conducted to explore the role and mechanism of nesfatin-1 in the VSMCs’ phenotypic switch and vascular remodeling in hypertension at integrative, organic, molecular, cellular and genetic levels, and especially investigating whether the interaction between YAP (Yes-associated protein) and PI3K/AKT signaling pathway is involved in the roles of nesfatin-1. This research is expected to clarify the role, mechanisms and molecular targets of nesfatin-1 in phenotypic switch of VSMCs and vascular remodeling in hypertension. It is hopeful to provide novel approaches and laboratory data for the prevention and treatment of hypertension.

血管重构在高血压及其并发症中起重要作用，血管平滑肌细胞（VSMCs）表型转换是高血压血管重构的始动因素。VSMCs表型转换的分子机制是迫切需要解决的关键问题。我们预实验结果显示高血压大鼠血浆、血管中膜nesfatin-1的表达显著增多，体外实验显示nesfatin-1促进VSMCs表型转换，提示nesfatin-1可能在VSMCs表型转换和高血压血管重构中起重要作用。本研究将从整体、器官、细胞分子和基因水平探讨nesfatin-1介导的VSMCs表型转换在高血压血管重构中的作用及机制，特别是探讨YAP（yes-associated protein）和PI3K/AKT信号通路的交互作用是否参与nesfatin-1的作用。本研究有望阐明nesfatin-1介导的VSMCs表型转换在高血压血管重构中的作用及分子机制，为防治高血压提供新思路和实验数据支持。

高血压是最常见的慢性非传染性疾病之一，发病率高，危害大，治疗效果不理想。如何有效预防和治疗高血压是临床医学和基础医学共同面对的重大医学难题，因此迫切需要阐明高血压的发病机制和寻找有效的高血压防治措施。病理性血管重构是高血压血管病变和循环功能失衡的主要病理基础，逆转或改善血管重构也成为高血压治疗的靶点之一。抑制血管平滑肌细胞表型转换引起的血管重构可能成为治疗高血压的策略之一，研究血管平滑肌细胞表型转换的特点、影响因素及分子机制对于治疗高血压和血管重构具有重要的临床意义。Nesfatin-1是来源于核组蛋白2(NUCB2)裂解后的产物，由82个氨基酸组成的肽段。过去研究显示nesfatin-1可能与血压调控存在密切联系，但其参与血压调控的机制尚未完全阐明。.本研究致力于探讨脂肪因子nesfatin-1调控血管平滑肌细胞表型转换和高血压血管重构的作用及分子机制。采用了对照组大鼠和自发性高血压大鼠、主动脉平滑肌细胞、原代血管平滑细胞培养、细胞基因敲减、药理学干预等实验技术，结果发现（1）自发性高血压大鼠外周血和胸主动脉血管中膜nesfatin-1的表达显著升高；（2）PI3K/Akt/mTOR和JAK2/STAT3信号通路参与了nesfatin-1介导的血管平滑肌细胞的表型转换和增殖，并且PI3K/Akt/mTOR信号通路和JAK2/STAT3信号通路之间的相互作用参与了nesfatin-1在血管平滑肌细胞的作用；（3）慢性长期腹腔注射nesfatin-1显著升高正常大鼠的血压并引起心血管重构，相反下调nesfatin-1有效降低自发性高血压大鼠的血压并改善心血管重构。该研究不仅有助于阐明nesfatin-1与高血压血管重构的关系，而且为防治高血压病奠定实验基础。