Elabela通过调控CMG2/Akt/GPX4铁死亡信号在高血压血管纤维化及血管损伤修复中作用机制研究

血管纤维化重构损伤是导致高血压心脑血管事件发生的病理生理学基础。我们前期研究提示，高血压状态下CMG2水平下调，伴有Apelin下调和血管损伤(FASEB J. 2021; Hypertension 2017)，但其机制不明。已证实Elabela（ELA）为Apelin受体另一个重要配体，参与心血管功能调控。为此我们提出假说，ELA通过调控CMG2及其下游PI3K/Akt信号，改善血管铁死亡信号，减轻高血压血管纤维化重构和功能损伤。本课题拟利用SHR高血压大鼠、ELA过表达、CMG2KO小鼠结合Ang II微泵及TAC术制备高血压血管损伤模型，采用ELA-32、Lenti-CMG2和铁死亡抑制剂Fer-1开展体内外实验，探讨ELA对高血压CMG2/Akt/NRF2、SLC7A11/GPX4铁死亡信号及脂质过氧化、炎症及纤维化重构的影响，为确立ELA作为高血压血管损伤早期防治新靶点提供科学依据。

Hypertension is a common vascular disease with high morbidity and mortality all over the world. Vascular fibrosis and remodeling injury are the pathophysiological basis of cardiovascular and cerebrovascular events in patients with hypertension. Apelin receptor APJ has been shown to be activated by a novel endogenous peptide ligand known as Elabela (ELA, also called Toddler or Apela), with an important role in cardiovascular development and function. Activation of APJ by its cognate peptide ligand ELA induces a wide range of physiological effects, including anti-hypertension, positive inotropic action, diuresis, anti-remodeling, anti-inflammatory, antifibrotic and cardiorenal protection. Our previous studies have demonstrated that there were marked downregulated levels of capillary morphogenesis gene 2 (CMG2) and Apelin during hypertension, accompanied by vascular injury and dysfunction (FASEB J. 2021; Hypertension 2017), but underlying mechanisms remain largely unknown. The ELA-APJ axis has been shown to involve in vascular injury and repairment. Therefore, we speculated that ELA may prevent ferroptosis in vascular tissue and improve vascular fibrosis and structural and functional damage in hypertension by modulating the CMG2/PI3K/Akt signaling. In this project, hypertensive SHR rats, ELA overexpression and CMG2 knockout mice were used combined with Ang II osmotic minipump and TAC operation to prepare hypertensive vascular injury animal models. Recombinant lenti-CMG2 and ferroptosis inhibitor Fer-1 were used to carry out in vitro and in vivo intervention experiments and to systematically explore the effects of ELA on ferroptosis, lipid peroxidation and inflammation and fibrotic remodeling of hypertensive animal model by regulating the CMG2/Akt/Nrf2 and SLC7A11/GPx4 signaling, providing scientific basis for establishing ELA as a new target for early prevention and treatment of hypertensive vascular injury.