Abstract 19889: 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 the expression of SM22α and contractile proteins but increased the expression of MMP2 and induced SMC phenotype switch, all of which were reduced by knocking down STING or IRF3. We found that ER stress, through STING, activated IRF3 that bound to the SM22α gene promoter and recruited histone deacetylase 4 (HDAC4), leading to promoter histone deacetylation and inhibition of myocardin/serum response factor-mediated SMC gene expression. Finally, in a sporadic mouse AAD model, challenging wild type mice with a high-fat diet and angiotensin II infusion induced significant SMC gene suppression and phenotype switch in both the thoracic and abdominal aorta. These changes were significantly reduced in Sting-deficient (Sting gt/gt) mice.
Conclusions: ER stress, through the STING-IRF3 pathway, epigenetically represses SMC genes and induces SMC phenotype switch. Thus, ER stress and the STING-IRF3 pathway may be potential therapeutic targets for preventing alteration of SMC phenotype in patients with sporadic aortic aneurysm.
Author Disclosures: Y. Mao: None. L. Zhang: None. P. Ren: None. S. Krishnamoorthy: None. M. Zhang: None. C. Guardado: None. J. Coselli: None. S. LeMaire: None. Y. Shen: None.
- © 2016 by American Heart Association, Inc.