Division of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, Unites States of America.
Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, Unites States of America.
PLoS One. 2022 Feb 25;17(2):e0264413. doi: 10.1371/journal.pone.0264413. eCollection 2022.
The caveolin-1 scaffolding domain (CSD, amino acids 82-101 of caveolin-1) has been shown to suppress bleomycin-induced lung and skin fibrosis and angiotensin II (AngII)-induced myocardial fibrosis. To identify active subregions within CSD, we split its sequence into three slightly overlapping 8-amino acid subregions (82-89, 88-95, and 94-101). Interestingly, all three peptides showed activity. In bleomycin-treated mice, all three subregions suppressed the pathological effects on lung and skin tissue morphology. In addition, while bone marrow monocytes isolated from bleomycin-treated mice showed greatly enhanced migration in vitro toward CXCL12, treatment in vivo with CSD and its subregions almost completely suppressed this enhanced migration. In AngII-induced heart failure, both 82-89 and 88-95 significantly suppressed fibrosis (both Col I and HSP47 levels), microvascular leakage, and heart weight/ body weight ratio (HW/BW) while improving ventricular function. In contrast, while 94-101 suppressed the increase in Col I, it did not improve the other parameters. The idea that all three subregions can be active depending on the assay was further supported by experiments studying the in vitro migration of human monocytes in which all three subregions were extremely active. These studies are very novel in that it has been suggested that there is only one active region within CSD that is centered on amino acids 90-92. In contrast, we demonstrate here the presence of other active regions within CSD.
窖蛋白-1 支架结构域（CSD，窖蛋白-1 的 82-101 位氨基酸）已被证明可抑制博来霉素诱导的肺和皮肤纤维化以及血管紧张素 II（AngII）诱导的心肌纤维化。为了鉴定 CSD 内的活性亚区，我们将其序列分成三个略有重叠的 8 个氨基酸亚区（82-89、88-95 和 94-101）。有趣的是，这三个肽段都具有活性。在博来霉素处理的小鼠中，所有三个亚区均抑制了肺和皮肤组织形态的病理效应。此外，虽然骨髓单核细胞在博来霉素处理的小鼠中表现出明显增强的体外向 CXCL12 的迁移，但体内用 CSD 及其亚区治疗几乎完全抑制了这种增强的迁移。在 AngII 诱导的心力衰竭中，82-89 和 88-95 均显著抑制纤维化（Col I 和 HSP47 水平）、微血管渗漏和心脏重量/体重比（HW/BW），同时改善心室功能。相比之下，虽然 94-101 抑制了 Col I 的增加，但它没有改善其他参数。这一观点认为，所有三个亚区都可以根据测定的方法发挥作用，这一观点得到了进一步的支持，因为在研究人类单核细胞体外迁移的实验中，所有三个亚区都具有极强的活性。这些研究非常新颖，因为人们曾认为 CSD 内只有一个活性区域，位于 90-92 位氨基酸之间。相比之下，我们在这里证明了 CSD 内存在其他活性区域。
