Golda Adam, Jurecka Agnieszka, Gajda Karolina, Tylki-Szymańska Anna, Lalik Anna
Department of Cardiology, Gliwice Medical Center, Gliwice, Poland.
Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.
Mol Genet Metab Rep. 2015 Feb 28;3:11-7. doi: 10.1016/j.ymgmr.2015.02.003. eCollection 2015 Jun.
Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal disorder caused by a deficient activity of N-acetylgalactosamine-4-sulfatase (ARSB). Pulmonary hypertension (PH) occurs in MPS VI patients and is a marker of bad prognosis. Malfunction of endothelium, which regulates vascular tonus and stimulates angiogenesis, can contribute to the occurrence of PH in MPS VI.
The aim of the study was to establish a human MPS VI cellular model of pulmonary artery endothelial cells (HPAECs) and evaluate how it affects factors that may trigger PH such as proliferation, apoptosis, expression of endothelial nitric oxide synthase (eNOS), natriuretic peptide type C (NPPC), and vascular endothelial growth factor A (VEGFA).
Increasing concentrations of dermatan sulfate (DS) reduce the viability of the cells in both ARSB deficiency and controls, but hardly influence apoptosis. The expression of eNOS in HPAECs is reduced up to two thirds in the presence of DS. NPPC shows a biphasic expression reaction with an increase at 50 μg/mL DS and reduction at 0 and 100 μg/mL DS. The expression of VEGFA decreases with increasing DS concentrations and absence of elastin, and increases with increasing DS in the presence of elastin.
Our data suggest that MPS VI endothelium presents a prohypertensive phenotype due to the reduction of endothelium's proliferation ability and expression of vasorelaxing factors.
黏多糖贮积症 VI 型（MPS VI）是一种常染色体隐性溶酶体疾病，由 N - 乙酰半乳糖胺 - 4 - 硫酸酯酶（ARSB）活性缺乏引起。MPS VI 患者会出现肺动脉高压（PH），且是预后不良的一个标志。调节血管张力并刺激血管生成的内皮功能障碍可能导致 MPS VI 患者发生 PH。
本研究旨在建立肺动脉内皮细胞（HPAECs）的人 MPS VI 细胞模型，并评估其如何影响可能引发 PH 的因素，如增殖、凋亡、内皮型一氧化氮合酶（eNOS）、C 型利钠肽（NPPC）和血管内皮生长因子 A（VEGFA）的表达。
硫酸皮肤素（DS）浓度增加会降低 ARSB 缺乏组和对照组细胞的活力，但对凋亡影响不大。在存在 DS 的情况下，HPAECs 中 eNOS 的表达降低了多达三分之二。NPPC 呈现双相表达反应，在 50 μg/mL DS 时增加，在 0 和 100 μg/mL DS 时降低。VEGFA 的表达在 DS 浓度增加且无弹性蛋白时降低，在有弹性蛋白存在时随 DS 增加而增加。
我们的数据表明，由于内皮细胞增殖能力和血管舒张因子表达降低，MPS VI 内皮呈现出促高血压表型。
