Tauroursodeoxycholic Acid Attenuates Angiotensin II Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E-deficient Mice by Inhibiting Endoplasmic Reticulum Stress

Abstract

Objective/background: Abdominal aortic aneurysm (AAA) is characterised by the infiltration of smooth muscle cell (SMC) apoptosis, inflammatory cells, neovascularisation, and degradation of the extracellular matrix. Previous work has shown that endoplasmic reticulum (ER) stress and SMC apoptosis were increased both in a mouse model and human thoracic aortic aneurysm. However, whether the ER stress is activated in AAA formation and whether suppressing ER stress attenuates AAA is unknown.

Methods: Human AAA and control aorta samples were collected. Expression of ER stress chaperones glucose-regulated protein (GRP)-78 and GRP-94 was detected by immunohistochemical staining. The effect of ER stress inhibitor tauroursodeoxycholic acid (TUDCA) on AAA formation in angiotensin (Ang) II induced apolipoprotein E^-/- mice was explored. Elastin staining was used to observe the rupture of elastic fragmentation. Immunohistochemistry and Western blot analysis were performed, to detect the protein expression of ER stress chaperones and apoptosis molecules.

Results: There was significant upregulation of GRP-78 and GRP-94 in aneurysmal areas of human AAA and Ang II induced ApoE^-/- mice (p < .05). TUDCA significantly attenuated the maximum diameters of abdominal aortas in Ang II induced ApoE^-/- mice (p < .05). TUDCA significantly reduced expression of ER stress chaperones and the apoptotic cell numbers (p < .05). Furthermore, TUDCA significantly reduced expression of apoptosis molecules, such as caspase-3, caspase-12, C/EBP homologous protein, c-Jun N-terminal kinase activating transcription factor 4, X-box binding protein, and eukaryotic initiation factor 2α in Ang II induced ApoE^-/- mice (p < .05).

Conclusion: The results suggest that ER stress is involved in human and Ang II induced AAA formation in ApoE^-/- mice. TUDCA attenuates Ang II induced AAA formation in ApoE^-/- mice by inhibiting ER stress mediated apoptosis.

Keywords: Abdominal aortic aneurysm; Apoptosis; Endoplasmic reticulum stress; Tauroursodeoxycholic acid.