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STING is Involved in the Development of Aortic Aneurysm and Dissection
Author(s) -
Guardado Christopher,
Zhang Lin,
Coselli Joseph S,
Shen Ying H,
LeMaire Scott A
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1119.14
Subject(s) - sting , cd68 , inflammation , biology , necroptosis , endoplasmic reticulum , angiotensin ii , medicine , pathology , microbiology and biotechnology , receptor , immunology , programmed cell death , immunohistochemistry , genetics , apoptosis , engineering , aerospace engineering
Objectives Aortic aneurysm and dissection (AAD) is associated with significant morbidity and mortality. Less than 20% of AAD cases are caused by genetic defects, whereas more than 80% are classified as sporadic. Sporadic AAD results from a progressive loss of smooth muscle cells in the tunica media. However, the molecular mechanisms that lead to the development and pathology of sporadic AAD remain poorly understood. STING (stimulator of interferon genes) is involved in inflammation in response to endoplasmic reticulum stress and DNA damage. Our preliminary data indicate that STING plays a critical role in AAD development. The objective of the current study was to elucidate the molecular pathways by which the STING‐mediated innate immune response contributes to the development of AAD. Methods and Results Eight‐week‐old Sting −/− mice and wild type mice were either challenged with a high‐fat diet for 8 weeks and an angiotensin II infusion during the last 4 weeks or remained unchallenged for the study period. Aortas from the Sting −/− and wild type mice were stained with markers for smooth muscle cells (SM22a), inflammatory cells (CD68 for macrophages, matrix metalloproteinase [MMP]‐2, and MMP‐9), fibroblasts (fibroblast‐specific protein 1 [FSP1]), and necroptosis (receptor‐interacting protein kinase 3 [RIP3] and mixed lineage kinase domain‐like protein [MLKL]). Qualitative analysis of the stained images showed that aortic challenge induced a significant decrease in the smooth muscle cell marker but increases in CD68, MMP‐2, FSP1, and RIP3 in the aortic smooth muscle cells in wild type mice. Importantly, these changes were significantly reduced in aortas from the challenged Sting −/− mice, as compared to those from challenged wild type mice. Conclusions Our study suggests that STING may contribute to a switch in smooth muscle cell phenotype and necroptosis, leading to a loss of smooth muscle cells during AAD development. Support or Funding Information Baylor College of Medicine and NIH grants