Maruyama Hidekazu, Sakai Satoshi, Dewachter Laurence, Dewachter Céline, Rondelet Benoit, Naeije Robert, Ieda Masaki
Department of Cardiology, National Hospital Organization Kasumigaura Medical Center, Tsuchiura, Japan.
Faculty of Health Science, Tsukuba University of Technology, Tsukuba, Japan.
Can J Physiol Pharmacol. 2020 Sep;98(9):629-636. doi: 10.1139/cjpp-2019-0658. Epub 2020 Jul 2.
The increase in thickening of the arterial wall of pulmonary arterial hypertension (PAH) includes cellular proliferation as well as matrix deposition and interrupted internal elastic lamina (IEL) consisting of a thick homogeneous sheet of elastin. Little is, although, known about the detail of IEL formation in PAH. Endothelin-1 is overexpressed in pulmonary arterioles of PAH. We aimed to examine the expression of genes contributing to IEL formation in pulmonary artery smooth muscle cells (PASMCs) especially focused on lysyl oxidase (LOx), an exreacellular matrix enzyme that catalyzes the cross-linking of collagens or elastin. We quantified mRNA expressions of genes contributing to IEL formation including LOx in PASMCs using real-time quantitative polymerase chain reaction. We stimulated human PASMCs with endothelin-1 with prostacyclin or trapidil. Endothelin-1 significantly increased LOx expression. Prostacyclin and trapidil restored endothelin-1-induced LOx expression to the basal level. Endothelin-1 increased LOx expression strongly in PASMCs from PAH patients compared to those from controls. Trapidil reduced LOx expression only in PASMCs from PAH patients. Overexpressed endothelin-1 in PAH patients can increase expression of LOx and agitate cross-linking of elastin and collagen, resulting in ectopic deposition of these in the vascular media.
肺动脉高压（PAH）时动脉壁增厚增加，包括细胞增殖、基质沉积以及由厚的均质弹性蛋白片组成的内弹力层（IEL）中断。然而，关于PAH中IEL形成的细节知之甚少。内皮素-1在PAH的肺小动脉中过度表达。我们旨在研究在肺动脉平滑肌细胞（PASMCs）中有助于IEL形成的基因的表达，特别关注赖氨酰氧化酶（LOx），一种催化胶原蛋白或弹性蛋白交联的细胞外基质酶。我们使用实时定量聚合酶链反应定量了PASMCs中有助于IEL形成的基因（包括LOx）的mRNA表达。我们用前列环素或曲匹地尔刺激人PASMCs与内皮素-1。内皮素-1显著增加LOx表达。前列环素和曲匹地尔将内皮素-1诱导的LOx表达恢复到基础水平。与对照组相比，内皮素-1在PAH患者的PASMCs中强烈增加LOx表达。曲匹地尔仅降低PAH患者PASMCs中的LOx表达。PAH患者中过度表达的内皮素-1可增加LOx表达并促进弹性蛋白和胶原蛋白的交联，导致这些物质在血管中层异位沉积。
