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      S-Nitrosylation of Plastin-3 Exacerbates Thoracic Aortic Dissection Formation via Endothelial Barrier Dysfunction.

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          Thoracic aortic dissection (TAD) is a fatal disease that leads to aortic rupture and sudden death. However, little is known about the effect and molecular mechanism of S-nitrosylation (SNO) modifications in TAD formation. Approach and Results: SNO levels were higher in aortic tissues from TAD patients than in those from healthy controls, and PLS3 (plastin-3) SNO was identified by liquid chromatography-tandem mass spectrometry analysis. Furthermore, tail vein administration of endothelial-specific adeno-associated viruses of mutant PLS3-C566A (denitrosylated form) suppressed the development of TAD in mice, but the wild-type PLS3 (S-nitrosylated form) virus did not. Mechanistically, Ang II (angiotensin II)-induced PLS3 SNO enhanced the association of PLS3 with both plectin and cofilin via an iNOS (inducible nitric oxide synthase)-dependent pathway in endothelial cells. The formation of PLS3/plectin/cofilin complex promoted cell migration and tube formation but weakened adherens junction formation in Ang II-treated endothelial cells. Interestingly, denitrosylated form of PLS3 partially mitigated Ang II-induced PLS3/plectin/cofilin complex formation and cell junction disruption. Additionally, the inhibition of iNOS attenuated PLS3 SNO and the association of PLS3 with plectin and cofilin, thereby modulating endothelial barrier function.

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          Author and article information

          Arterioscler Thromb Vasc Biol
          Arteriosclerosis, thrombosis, and vascular biology
          Ovid Technologies (Wolters Kluwer Health)
          January 2020
          : 40
          : 1
          [1 ] From the Key Laboratory of Cardiovascular and Cerebrovascular Medicine, State Key Laboratory of Reproductive Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, China (L.P., Z.L., X.T., J.T., Q.Z., L.X., H.C., Y.J.).
          [2 ] Department of Cardiovascular Center, The Second Affiliated Hospital of Nanjing Medical University, China (J.J., Q.L.).
          [3 ] Center for Metabolic Disease Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (H.W.).
          [4 ] Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, China (Q.L.).
          [5 ] Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, China (Y.H.).

          aneurysm,mass spectrometry,angiotensin II,endothelial cells,plectin


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