Wei Luo1,2, Yidan Wang1,2, Lin Zhang1,2, Pingping Ren1,2, Chen Zhang1,2, Yanming Li1,2, Alon R Azares3, Michelle Zhang1, Jiao Guo1,2, Ketan B Ghaghada4, Zbigniew A Starosolski4, Kimal Rajapakshe5, Cristian Coarfa6, Yumei Li7, Rui Chen8,9,7, Keigi Fujiwara10, Jun-Ichi Abe10, Joseph S Coselli11,1,2, Dianna M Milewicz12, Scott A LeMaire11,1,2, Ying H Shen11,1,2. 1. Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (W.L., Y.W., L.Z., P.R., C.Z., Yanming Li, M.Z., J.G., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX. 2. Department of Cardiovascular Surgery (W.L., Y.W., L.Z., P.R., C.Z., Yanming Li, J.G., J.S.C., S.A.L., Y.H.S.), Texas Heart Institute, Houston. 3. Molecular Cardiology Research Lab (A.R.A.), Texas Heart Institute, Houston. 4. Department of Pediatric Radiology, Texas Children's Hospital, Houston (K.B.G., Z.A.S.). 5. Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, TX. 6. Dan L. Duncan Cancer Center (C.C.), Baylor College of Medicine, Houston, TX. 7. Human Genome Sequencing Center (Yumei Li, R.C.), Baylor College of Medicine, Houston, TX. 8. Department of Biochemistry and Molecular Biology (R.C.), Baylor College of Medicine, Houston, TX. 9. Department of Molecular and Human Genetics (R.C.), Baylor College of Medicine, Houston, TX. 10. Department of Biostatistics and Division of Internal Medicine, Department of Cardiology Research, The University of Texas MD Anderson Cancer Center, Houston (K.F., J.A.). 11. Cardiovascular Research Institute (J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX. 12. Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M.).
Abstract
BACKGROUND: Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation. METHODS: The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in Sting-deficient (Stinggt/gt) mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro. RESULTS: In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, Stinggt/gt mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged Stinggt/gt mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development. CONCLUSIONS: Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.
BACKGROUND:Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation. METHODS: The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in Sting-deficient (Stinggt/gt) mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro. RESULTS: In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, Stinggt/gt mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged Stinggt/gt mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development. CONCLUSIONS: Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.
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