W. Luo1,2, Y. Wang1,2, L. Zhang1,2, P. Ren1,2, C. Zhang1,2, J. Guo1,2, C. Joseph S1,2,3, Y. Shen1,2,3, S. LeMaire1,2,3 1Baylor College Of Medicine,Division Of Cardiothoracic Surgery,Houston, TX, USA 2Texas Heart Institute,Department Of Cardiovascular Surgery,Houston, TX, USA 3Baylor College Of Medicine,Cardiovascular Research Institute,Houston, TX, USA
Introduction: Aortic aneurysm and dissection (AAD) carries significant morbidity and mortality. One of the significant features of AAD is progressive smooth muscle cell (SMC) dysfunction and depletion, which leads to aortic dilatation, biomechanical failure, and ultimately rupture. However, the molecular mechanisms underlying the progressive SMC dysfunction and depletion are poorly understood. Increasing evidence has suggested a critical role of endoplasmic reticulum (ER) stress in cell dysfunction. However, whether ER stress can promote aortic destruction, dysfunction and AAD development is unknown. In this study, we examined the effect of ER stress on aortic destruction and AAD formation in mice.
Methods: The activation of ER stress was compared in aortic tissues from patients with sporadic ascending thoracic AAD with that in tissues from age-matched organ donor controls. The contribution of ER stress to AAD development was assessed by comparing AAD development in C57BL/6J mice that were given thapsigargin (Tg) (n=39) or vehicle (n=40) before challenged with low-dose angiotensin infusion (AngII, 1000 ng/min/kg) for four weeks.
Results: We observed significant upregulation of ER stress markers in patient aortic tissues, especially in smooth muscle cell (SMC). Thapsigargin itself did not cause AAD or dilatation. However, thapsigargin significantly increased the challenge-induced incidence of AAD (15% in challenged mice vs 44% in Tg treated challenged mice, p=0.005), severe AAD (8% in challenged mice vs 23% in Tg treated challenged mice, p=0.05). Thapsigargin showed similar effect in male and female mice. Furthermore, aortic tissues from challenged mice treated with Tg showed markedly increased aortic destruction and elastic fiber fragmentation.
Conclusion: Our findings demonstrate that inducing ER stress with thapsigargin increases susceptibility to sporadic aortic aneurysm and dissection in mice.