Critical Role of Endoplasmic Reticulum Stress-STING-IRF3 Pathway in Smooth Muscle Cell Phenotype Switch in Aortic Aneurysm and Dissection

Introduction: A significant feature of sporadic aortic aneurysm and dissection (AAD) development is smooth muscle cell (SMC) phenotype switch that results in SMC contractile dysfunction. Endoplasmic reticulum (ER) stress and the ER stress sensor pathway—STING (stimulator of interferon genes)-IRF3 (interferon regulatory factor-3)—induce cellular inflammatory responses. Hypothesis: The ER stress-STING-IRF3 pathway induces SMC inflammatory responses and phenotype switch in sporadic AAD. Methods and Results: In human sporadic thoracic AAD tissues, we observed significant SMC phenotype switch characterized by reduced expression of the SMC marker, SM22α, and contractile proteins (tropomyosin and myosin heavy chain) but increased expression of matrix metalloproteinase-2 (MMP2) and the fibroblast marker, fibroblast-specific protein-1 (FSP1), in SMCs. SMC phenotype switch was associated with activation of ER stress and the STING-IRF3 pathway. In cultured SMCs, the ER stress activator thapsigargin (Tg) suppressed t...