Abstract
Abdominal aorta aneurysm (AAA) is a major cause of mortality in men. The role of endoplasmic reticulum (ER) stress in the pathogenesis of AAA is unknown. Human AAA specimens from diabetic patients were found to have increased expression of ER stress markers. The inhibition of ER stress signaling with (taurine-conjugated ursodeoxycholic acid, Tudca) administration reduces the development of aneurysm in Ang-II infused and calcium chloride (CaCl2)-induced mouse models. Type 2 diabetic (db-/db-) and control (db-/db+) mice were infused with angiotensin II (Ang-II, 1000ng/kg/min) and treated with or without the ER stress inhibitor Tudca for 4 weeks. Mice infused with Ang-II displayed an increase in blood pressure, plasma cholesterol and CRP levels, which were reduced after ER stress inhibition. Human AAA and Ang-II-induced AAA are characterized by an increase in lumen, cross sectional area and were associated with increased macrophage infiltration, expression of the ER stress marker CHOP and elastic fiber disruption, and these indicators of aneurysm disease were reduced by Tudca treatment. To determine the effect of ER stress inhibition on aneurysm formation in a model that did not exhibit blood pressure and metabolic changes, we exposed the adventitial surface of carotid arteries of db-/db- and db-/db+ mice to CaCl2 and then treated the mice with or without Tudca. Our results indicate that in the CaCl2 induced carotid artery aneurysm model that treatment with Tudca significantly reduced carotid artery aneurysm formation. These results provide evidence in support of a role for that ER stress activation in the induction of aneurysm in type 2 diabetes.
Published Version
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