The Effect Of Endoplasmic Reticulum Stress Mediated C/EBP Homologous Protein Activation In The Pathogenesis Of Abdominal Aortic Aneurysm

Objective:Abdominal aortic aneurysm(AAA) is an aortic disease with high mortality rate after rupture. Studies indicated that AAA is closely related with abdominal aortic smooth muscle cells(SMC) apoptosis and inflammation. Previous studies have documented endoplasmic reticulum(ER) stress participates in the pathogenesis of atherosclerosis, heart failure and other cardiovascular diseases by activating C/EBP homologous protein(CHOP)- mediated apoptosis and inflammation. However, whether there's a link between AAA and ER stress has yet not been documented. Therefore, in this experimental study, we further clarify the role of endoplasmic reticulum stress and CHOP in abdominal aortic aneurysm in order to improve the pathogenesis of abdominal aortic aneurysms. we observe the reaction of the endoplasmic reticulum stress pathway and CHOP protein intervened by ER stress protectant, so as to provide new ideas for the prevention and treatment of abdominal aortic aneurysms. Methods:We detect the activation of endoplasmic reticulum stress and CHOP protein in vascular tissue of abdominal aortic aneurysm patients by Western blotting. In AngII induced APOE knockout mouse animal model of abdominal aortic aneurysm, We detect the activation of endoplasmic reticulum stress and CHOP protein by immunohistochemistry and Western blotting. And we detect the reaction of the endoplasmic reticulum stress and CHOP protein intervened by ER stress protectant TUDCA or PBA. After the intervention, we observe whether it can alleviate the endoplasmic reticulum stress response and inhibit the expression of CHOP protein. In further experiments, we detect cell apoptosis and tissue inflammation situation in the mouse aorta by immunohistochemistry and Western blotting. Results:In vascular tissue of abdominal aortic aneurysm patients, the expression of endoplasmic reticulum stress marker protein GRP78 increases, while PERK phosphorylation level also increases. Further studies have shown that expression of apoptosis-related protein CHOP significantly increases. In Ang II induced APOE knockout mouse animal model of abdominal aortic aneurysm, the administration of angiotensin II could induce mice forming abdominal aortic aneurysms. We observe increasing incidence of aneurysm, significantly expanding arterial diameter, thickening of the arterial wall. Also, elastin fibers of the arterial wall are degraded with irregular or partial rupture. By immunohistochemistry and Western blot detecting, the expressions of GRP78, ATF4, eIF2?, XBP-1 obviously increase, and the expression level of apoptosis-related protein CHOP significantly increases. In TUNEL assay, apoptotic cells also increase significantly. By immunohistochemistry and Western blot detecting, expression of caspase3 increases, while the expression of apoptosis-related BAX is up regulated, compared to anti-apoptotic protein Bcl-2 is down regulated. Inflammatory cytokines(IL-1?, IL-6, IL-8) expression levels significantly increase, and the expression of the macrophage marker CD68 protein significantly also increased. However, after administrationof the endoplasmic reticulum stress protectant TUDCA or PBA, the formation of abdominal aortic aneurysms in mice is significantly inhibited, and the endoplasmic reticulum stress response and CHOP protein expression are significantly reduced. At the same time, the expression of apoptosis-related proteins decrease, as well as the secretion of inflammatory cytokines and macrophage infiltration reduce. Conclusion:In vascular tissue of abdominal aortic aneurysm patients, the endoplasmic reticulum stress response and CHOP protein are activated. In AngII induced APOE knockout mouse animal model of abdominal aortic aneurysm, the endoplasmic reticulum stress response and CHOP protein is activated. After administrationof the endoplasmic reticulum stress protectant TUDCA or PBA, it can alleviate the endoplasmic reticulum stress response and inhibit the expression of CHOP protein. In AngII induced APOE knockout mouse animal model of abdominal aortic aneurysm, endoplasmic reticulum stress response induce increaseing apoptosis in mice abdominal aorta. After administrationof protectant TUDCA or PBA, it can alleviate aortic cells apoptosis. In AngII induced APOE knockout mouse animal model of abdominal aortic aneurysm, endoplasmic reticulum stress response induce enhancing inflammation in mice abdominal aorta. After administrationof protectant TUDCA or PBA, it can alleviate aortic tissue infammation.