Laboratoire de Biochimie Médicale et Biologie Moléculaire, CNRS/URCA UMR N° 7369 MEDyC Matrice Extracellulaire et Dynamique Cellulaire, Team 2 "Matrix Aging and Vascular Remodeling", Faculté de Médecine, University of Reims Champagne-Ardenne, 51 Rue Cognacq-Jay, 51095, Reims, France.
LRN EA 4682 Laboratoire de Recherche en Nanosciences and NanoMat' Platform, University of Reims Champagne-Ardenne, Reims, France.
Sci Rep. 2021 Sep 8;11(1):17827. doi: 10.1038/s41598-021-97293-5.
Because of their long lifespan, matrix proteins of the vascular wall, such as elastin, are subjected to molecular aging characterized by non-enzymatic post-translational modifications, like carbamylation which results from the binding of cyanate (mainly derived from the dissociation of urea) to protein amino groups. While several studies have demonstrated a relationship between increased plasma concentrations of carbamylated proteins and the development of cardiovascular diseases, molecular mechanisms explaining the involvement of protein carbamylation in these pathological contexts remain to be fully elucidated. The aim of this work was to determine whether vascular elastic fibers could be carbamylated, and if so, what impact this phenomenon would have on the mechanical properties of the vascular wall. Our experiments showed that vascular elastin was carbamylated in vivo. Fiber morphology was unchanged after in vitro carbamylation, as well as its sensitivity to elastase degradation. In mice fed with cyanate-supplemented water in order to increase protein carbamylation within the aortic wall, an increased stiffness in elastic fibers was evidenced by atomic force microscopy, whereas no fragmentation of elastic fiber was observed. In addition, this increased stiffness was also associated with an increase in aortic pulse wave velocity in ApoE mice. These results provide evidence for the carbamylation of elastic fibers which results in an increase in their stiffness at the molecular level. These alterations of vessel wall mechanical properties may contribute to aortic stiffness, suggesting a new role for carbamylation in cardiovascular diseases.
由于血管壁基质蛋白（如弹性蛋白）的寿命较长，因此会经历分子衰老，其特征是非酶翻译后修饰，如氨甲酰化，这是由氰酸盐（主要来源于尿素的分解）与蛋白质氨基结合所致。虽然有几项研究表明，血浆中氨甲酰化蛋白浓度的增加与心血管疾病的发生有关，但解释蛋白氨甲酰化在这些病理情况下的参与的分子机制仍有待充分阐明。本研究旨在确定血管弹性纤维是否可发生氨甲酰化，如果可以，这种现象会对血管壁的机械性能产生什么影响。我们的实验表明，血管弹性蛋白在体内发生了氨甲酰化。纤维形态在体外氨甲酰化后没有改变，其对弹性蛋白酶降解的敏感性也没有改变。在给予富含氰酸盐的水以增加主动脉壁内蛋白质氨甲酰化的小鼠中，原子力显微镜显示弹性纤维的刚度增加，而没有观察到弹性纤维的碎片化。此外，这种刚度的增加与载脂蛋白 E 小鼠的主动脉脉搏波速度增加有关。这些结果为弹性纤维的氨甲酰化提供了证据，这导致其在分子水平上的刚度增加。这些血管壁机械性能的改变可能导致主动脉僵硬，提示氨甲酰化在心血管疾病中的新作用。
