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.

中文翻译：

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Plastin-3的S-亚硝基化可通过内皮屏障功能障碍加重胸主动脉夹层的形成。

目的胸主动脉夹层（TAD）是一种致命疾病，会导致主动脉破裂和猝死。但是，关于TAD形成中S-亚硝基化（SNO）修饰的作用和分子机理知之甚少。方法和结果：TAD患者的主动脉组织中的SNO水平高于健康对照者，并且通过液相色谱-串联质谱分析鉴定出PLS3（plastin-3）SNO。此外，尾静脉给予突变型PLS3-C566A（脱亚硝化形式）的内皮特异性腺相关病毒可抑制小鼠中TAD的发育，而野生型PLS3（S-亚硝化形式）则没有。机械上，血管紧张素II（血管紧张素II）诱导的PLS3 SNO通过iNOS（诱导型一氧化氮合酶）依赖性途径增强了内皮细胞中PLS3与Plectin和cofilin的结合。PLS3 / plectin / cofilin复合物的形成促进了细胞迁移和管形成，但减弱了经Ang II处理的内皮细胞的粘附连接形成。有趣的是，PLS3的去亚硝化形式可部分缓解Ang II诱导的PLS3 / plectin / cofilin复合物形成和细胞连接破坏。另外，iNOS的抑制会减弱PLS3 SNO以及PLS3与Plectin和Cofilin的结合，从而调节内皮屏障功能。结论我们的数据表明内皮细胞中蛋白质SNO的修饰可调节主动脉瘤和夹层的进展。