Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, and University of Pavia.
Department of Internal Medicine, Nephrology, Dialysis and Transplantation Clinics, Genoa University and IRCCS Ospedale Policlinico San Martino.
J Atheroscler Thromb. 2020 Oct 1;27(10):1039-1052. doi: 10.5551/jat.51144. Epub 2020 Mar 14.
Myostatin (Mstn) has been described as a trigger for the progression of atherosclerosis. In this study, we evaluated the role of Mstn in arterial remodeling in patients with end-stage renal disease (ESRD).
Vascular specimens were collected from 16 ESRD patients (56.4±7.9 years) undergoing renal transplant (recipients) and 15 deceased kidney non-uremic donors (55.4±12.1 years). We studied gene and protein expression of Mstn, ubiquitin ligases, Atrogin-1, and muscle ring finger protein-1 (MuRF-1), inflammatory marker CCL2, cytoskeleton components, and Klotho by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Moreover, we assessed vascular calcification and collagen deposition. Finally, we studied the effects of recombinant Mstn on rat vascular smooth muscle cells (VSMCs, A7r5) and evaluated the effects of uremic serum (US) on primary human VSMCs.
Myostatin mRNA was upregulated in the arterial vascular wall of recipients compared with donors (~15- folds, p＜0.05). This response was accompanied by the upregulation of gene expression of Atrogin-1 and MuRF-1 (＋2.5- and ＋10-fold) and CCL2 (＋3-fold). Conversely, we found downregulation of protein expression of Smoothelin, α-smooth muscle actin (α-SMA), vimentin, and Klotho (-85%, -50%, -70%, and -80%, respectively; p＜0.05) and gene expression of vimentin and Klotho. Exposition of A7r5 to Mstn induced a time-dependent SMAD 2/SMAD 3 phosphorylation and expression of collagen-1 and transforming growth factor β (TGFβ) mRNA, while US induced overexpression of Mstn and Atrogin-1 and downregulation of Smoothelin and Klotho.
Our data suggest that uremia might induce vascular Mstn gene expression together with a complex pathway of molecular and structural changes in the vascular wall. Myostatin, in turn, can translate the metabolic alterations of uremia into profibrotic and stiffness inducing signals.
肌肉生长抑制素（Mstn）已被描述为动脉粥样硬化进展的触发因素。在这项研究中，我们评估了 Mstn 在终末期肾病（ESRD）患者动脉重塑中的作用。
从 16 名接受肾移植（受者）的 ESRD 患者（56.4±7.9 岁）和 15 名已故非尿毒症供体的血管标本（55.4±12.1 岁）中收集血管标本。我们通过逆转录聚合酶链反应（RT-PCR）和免疫组织化学研究了 Mstn、泛素连接酶、Atrogin-1 和肌肉环指蛋白-1（MuRF-1）、炎症标志物 CCL2、细胞骨架成分和 Klotho 的基因和蛋白表达。此外，我们评估了血管钙化和胶原蛋白沉积。最后，我们研究了重组 Mstn 对大鼠血管平滑肌细胞（VSMCs，A7r5）的影响，并评估了尿毒症血清（US）对原代人 VSMCs 的影响。
与供体相比，受者动脉血管壁中的 Mstn mRNA 上调（约 15 倍，p＜0.05）。这种反应伴随着 Atrogin-1 和 MuRF-1 的基因表达上调（＋2.5-和＋10 倍）和 CCL2 的上调（＋3 倍）。相反，我们发现 Smoothelin、α-平滑肌肌动蛋白（α-SMA）、波形蛋白和 Klotho 的蛋白表达下调（分别为-85%、-50%、-70%和-80%，p＜0.05）和 vimentin 和 Klotho 的基因表达下调。A7r5 暴露于 Mstn 诱导 SMAD 2/SMAD 3 磷酸化和胶原-1 和转化生长因子β（TGFβ）mRNA 的时间依赖性表达，而 US 诱导 Mstn 和 Atrogin-1 的过表达以及 Smoothelin 和 Klotho 的下调。
我们的数据表明，尿毒症可能会诱导血管 Mstn 基因表达，同时伴有血管壁分子和结构变化的复杂途径。反过来，肌肉生长抑制素可以将尿毒症的代谢改变转化为致纤维化和诱导僵硬的信号。
