氮氧化物4
纤维蛋白
马凡氏综合征
NADPH氧化酶
主动脉
主动脉瘤
化学
血管平滑肌
中膜
内科学
病理
细胞生物学
医学
内分泌学
氧化应激
生物
颈动脉
平滑肌
作者
Francesc Jiménez‐Altayó,Thayna Meirelles,Eva Crosas‐Molist,Maria Alba Sorolla,Darya Gorbenko del Blanco,Judit López-Luque,Aleksandra Mas‐Stachurska,Ana-Maria Siegert,Fabio Bonorino,Laura Barberá,Carolina Miguel García,Enric Condom,Marta Sitges,Fernando Rodrı́guez-Pascual,Francisco Rafael Martins Laurindo,Katrin Schröder,Joaquim Ros,Isabel Fabregat,Gustavo Egea
标识
DOI:10.1016/j.freeradbiomed.2018.02.023
摘要
Marfan syndrome (MFS) is characterized by the formation of ascending aortic aneurysms resulting from altered assembly of extracellular matrix fibrillin-containing microfibrils and dysfunction of TGF-β signaling. Here we identify the molecular targets of redox stress in aortic aneurysms from MFS patients, and investigate the role of NOX4, whose expression is strongly induced by TGF-β, in aneurysm formation and progression in a murine model of MFS. Working models included aortae and cultured vascular smooth muscle cells (VSMC) from MFS patients, and a NOX4-deficient Marfan mouse model (Fbn1C1039G/+-Nox4-/-). Increased tyrosine nitration and reactive oxygen species levels were found in the tunica media of human aortic aneurysms and in cultured VSMC. Proteomic analysis identified nitrated and carbonylated proteins, which included smooth muscle α-actin (αSMA) and annexin A2. NOX4 immunostaining increased in the tunica media of human Marfan aorta and was transcriptionally overexpressed in VSMC. Fbn1C1039G/+-Nox4-/- mice aortas showed a reduction of fragmented elastic fibers, which was accompanied by an amelioration in the Marfan-associated enlargement of the aortic root. Increase in the contractile phenotype marker calponin in the tunica media of MFS mice aortas was abrogated in Fbn1C1039G/+-Nox4-/- mice. Endothelial dysfunction evaluated by myography in the Marfan ascending aorta was prevented by the absence of Nox4 or catalase-induced H2O2 decomposition. We conclude that redox stress occurs in MFS, whose targets are actin-based cytoskeleton members and regulators of extracellular matrix homeostasis. Likewise, NOX4 have an impact in the progression of the aortic dilation in MFS and in the structural organization of the aortic tunica media, the VSMC phenotypic modulation, and endothelial function.
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