Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, 41012, Seville, Spain.
Epidemiología Clínica y Riesgo Cardiovascular, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/Universidad de Sevilla, 41013, Seville, Spain.
J Physiol Biochem. 2022 Nov;78(4):915-932. doi: 10.1007/s13105-022-00916-2. Epub 2022 Aug 9.
Arterial hypertension (AH) leads to oxidative and inflammatory imbalance that contribute to fibrosis development in many target organs. Here, we aimed to highlight the harmful effects of severe AH in the cornea. Our experimental model was established by administration of NG-nitro-L-arginine-methyl-ester (L-NAME) to C57BL/6 mice, which were monitored weekly for arterial blood pressure and intraocular pressure (IOP). Morphological studies of ocular tissues were accompanied by analyses of reactive oxygen species generation, and localization/expression of NAPDH oxidase isoforms (NOX1, NOX2, NOX4) and inflammatory biomarkers (PPARα, PPARγ, IL-1β, IL-6, IL-10, TNF-α, and COX-2). Masson's trichrome and Sirius Red staining were used to explore the fibrotic status of the cornea. The expression of collagen isoforms (COL1α1, COL1α2, COL3α1, COL4α1, COL4α2) and relevant metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) were also quantified to evaluate the participation of collagen metabolism in AH-related corneal damage. Hypertensive animals showed an increase in IOP values, and a thinner cornea compared with normotensive controls. Moreover, AH increased NADPH oxidase activity and reactive oxygen species generation in the cornea, which was accompanied by transcriptional upregulation of NOX isoforms and inflammatory biomarkers, while reducing PPAR expression. L-NAME-treated animals also developed corneal fibrosis with overexpression of collagen isoforms and reduction of factors responsible for collagen degradation. This is the first study reporting structural changes in the cornea and elevated IOP in L-NAME-treated mice. Overexpression of the NADPH oxidase system and collagen deposition might play a substantial role in the pathogenic mechanisms contributing to ocular disturbances in a context of severe hypertension.
动脉高血压（AH）导致氧化和炎症失衡，这会促使许多靶器官发生纤维化。在这里，我们旨在强调严重 AH 对角膜的有害影响。我们的实验模型是通过给 C57BL/6 小鼠施用 NG-硝基-L-精氨酸甲酯（L-NAME）建立的，每周监测一次动脉血压和眼内压（IOP）。眼部组织的形态学研究伴随着活性氧生成的分析，以及 NADPH 氧化酶同工型（NOX1、NOX2、NOX4）和炎症生物标志物（PPARα、PPARγ、IL-1β、IL-6、IL-10、TNF-α 和 COX-2）的定位/表达。Masson 三色和 Sirius Red 染色用于探索角膜的纤维化状态。还定量评估了胶原同工型（COL1α1、COL1α2、COL3α1、COL4α1、COL4α2）和相关金属蛋白酶（MMPs）及其组织抑制剂（TIMPs）的表达，以评估胶原代谢在 AH 相关角膜损伤中的参与。与正常血压对照相比，高血压动物的 IOP 值升高，角膜变薄。此外，AH 增加了角膜中的 NADPH 氧化酶活性和活性氧生成，这伴随着 NOX 同工型和炎症生物标志物的转录上调，同时降低了 PPAR 的表达。用 L-NAME 处理的动物还发生了角膜纤维化，表现为胶原同工型的过度表达和胶原降解因子的减少。这是第一项报道 L-NAME 处理的小鼠角膜结构改变和 IOP 升高的研究。NADPH 氧化酶系统和胶原沉积的过度表达可能在严重高血压引起的眼功能障碍的发病机制中起重要作用。
