S-Nitrosylation of Plastin-3 Exacerbates Thoracic Aortic Dissection Formation via Endothelial Barrier Dysfunction. Issue 1 (January 2020)

• Record Type: Journal Article
• Authors: Pan, Lihong; Lin, Zhe; Tang, Xin; Tian, Jiaxin; Zheng, Qiao; Jing, Jin; Xie, Liping; Chen, Hongshan; Lu, Qiulun; Wang, Hong; Li, Qingguo; Han, Yi; Ji, Yong
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 40:Issue 1(2020)
• Publication Date: 2020-01
• Subjects: aneurysm -- angiotensin II -- endothelial cells -- mass spectrometry -- plectin; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.119.313440
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : Objective: 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. Conclusions: Our data indicate that protein SNO modification in endothelial cells modulates the progression of aortic aneurysm and dissection. The iNOS-mediated SNO of PLS3 at the Cys566 site promoted its interaction with cofilin and plectin, thus contributing to endothelial barrier disruption and pathological angiogenesis in TAD. Abstract : Supplemental Digital Content is available in the text.