血管紧张素（1-7）抗应激性胃粘膜损伤的机制研究

Adverse or excessive stress greatly threatens human health, like stress ulcer,which makes its prophylaxis and therapy a hot topic. Renin-angiotensin system is one of the important sessions involved in the regulation of stress response.Angiotensin (1-7) (Ang(1-7)) , an endogenous constituent of the body, play protective roles in many organs, but no reports in stomach. Moreover, it has been evidenced indirectly that Ang(1-7) possesses anti-stress activities. In our recent studies, Ang(1-7) protected against stress-induced gastric lesions, which is one of the first reports about this in the world. We also speculate that this gastroprotection arise from the recovery and conservation of hippocampal modulation as well as gastric defense-attack system. In the present study, it is therefore hypothesized that Ang(1-7) exert anti-ischemic and anti-oxidant activities during cold restraint stress via the downstream effector nitric oxide, which protects for hippocampal integrity and gastric defense system(for example, gastric blood flow and anti-oxidant activities ) , as well as gastric damage factors(for example, gastric acid and pepsin). These gastroprotective mechanisms will be uncovered through animal and culture investigation. These studies will provide a novel strategy for integrative prophylaxis and therapy of stress-induced gastric lesions, and share the novel findings from China with others in the field of stress-related disorders.

不良或过度应激严重影响人们的健康，因此对应激性损伤的预防与控制成为热门话题。肾素-血管紧张素系统是协调应激反应的重要环节。体内的血管紧张素(1-7)(Ang(1-7))具有多器官保护作用，但对胃粘膜的保护作用未见报道。研究表明Ang(1-7)可能具有抗应激作用。最近我们率先报道Ang(1-7)具有抗应激性胃粘膜损伤作用，并推测这种作用一方面来源于对海马这一应激调控中枢的保护及修复，另一方面来源于对胃粘膜防御-侵蚀失衡状态的修复。为验证上述推测，本项目拟通过动物实验及离体细胞培养证明Ang(1-7)可通过一氧化氮等机制，发挥抗缺血、抗氧化等作用，从而修复应激时海马结构及功能，并修复胃粘膜的屏障系统(胃粘膜血供、抗氧化能力等)，降低侵蚀因素（胃酸、胃蛋白酶），最终发挥抗应激性胃粘膜损伤作用。本项目如实现，将为应激性胃粘膜损伤的综合防治提供策略，并使我国应激性损伤的研究走在世界前列。

不良或过度应激严重影响人们的健康，因此对应激性损伤的预防与控制成为热门话题。肾素-血管紧张素系统是协调应激反应的重要环节。体内的血管紧张素(1-7)(Ang(1-7))具有多器官保护作用，研究表明Ang(1-7)可能具有抗应激作用，我们曾报道Ang(1-7)具有抗应激性胃粘膜损伤作用，但Ang(1-7)对应激调控中枢-海马的作用尚未见报道。在本研究中，我们一方面通过动物实验研究Ang(1-7)对海马的保护及其在胃粘膜修复的作用，另一方面通过离体细胞实验研究Ang(1-7)在缺氧再灌注应激下对胃粘膜上皮细胞的保护作用及机制。我们发现Ang(1-7)可通过一氧化氮修复应激时海马CA3区结构及功能，并修复胃粘膜及胃上皮的屏障系统(如胃粘膜血供、抗氧化能力等)，降低侵蚀因素（胃酸输出、胃蛋白酶活性），最终发挥抗应激性胃粘膜损伤作用。 同时，我们发现Ang(1-7)可通过抗凋亡、抗氧化、抗炎症等机制对缺氧再灌注损伤下的人胃粘膜上皮细胞发挥保护作用。因此，Ang(1-7)可间接通过修复应激调控中枢-海马，亦可直接通过保护胃粘膜上皮细胞，为胃粘膜提供显著的保护作用。由此Ang(1-7)可作为未来预防和治疗各种情况下，尤其是应激情况下胃粘膜损伤的重要药物，具有广阔的应用前景。