Cerecedo Doris, Martínez-Vieyra Ivette, Hernández-Rojo Isaac, Hernández-Cruz Arturo, Rincón-Heredia Ruth, Millán-Aldaco Diana, Mendoza-Garrido Maria Eugenia
Laboratorio de Hematobiología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Mexico City, Mexico.
Laboratorio de Hematobiología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Mexico City, Mexico.
Exp Cell Res. 2023 Dec 15;433(2):113847. doi: 10.1016/j.yexcr.2023.113847. Epub 2023 Nov 4.
Hypertension is a multifactorial disease characterized by vascular and renal dysfunction, cardiovascular remodeling, inflammation, and fibrosis, all of which are associated with oxidative stress. We previously demonstrated cellular reactive oxygen species (ROS) imbalances may impact the structural and biochemical functions of blood cells and reported downregulation of β-dystroglycan (β-Dg) and overexpression of the epithelial sodium channel (ENaC) contribute to the pathophysiology of hypertension. In this study, we aimed to determine the expression of dystroglycans (Dg) and ENaC in platelet progenitors (megakaryocytes) and their surrounding niches. Thin sections of bone marrow from 5- and 28-week-old spontaneous hypertensive rats (SHR) were compared to age-matched normotensive rats (WKY). Cytometry and immunohistochemical assays demonstrated an oxidative environment in SHR bone marrow, characterized by high levels of myeloperoxidase and 3-nitrotyrosine and downregulation of peroxiredoxin II. In addition, transmission electron micrography and confocal microscopy revealed morphological changes in platelets and Mgks from SHR rats, including swollen mitochondria. Quantitative qRT-PCR assays confirmed downregulation of Dg mRNA and immunohistochemistry and western-blotting validated low expression of β-Dg, mainly in the phosphorylated form, in Mgks from 28-week-old SHR rats. Moreover, we observed a progressive increase in β-1 integrin expression in Mgks and extracellular matrix proteins in Mgk niches in SHR rats compared to WKY controls. These results indicate accumulation of ROS promotes oxidative stress within the bone marrow environment and detrimentally affects cellular homeostasis in hypertensive individuals.
高血压是一种多因素疾病，其特征为血管和肾功能障碍、心血管重塑、炎症和纤维化，所有这些都与氧化应激有关。我们之前证明细胞活性氧（ROS）失衡可能影响血细胞的结构和生化功能，并报道β-肌营养不良聚糖（β-Dg）的下调和上皮钠通道（ENaC）的过表达有助于高血压的病理生理学。在本研究中，我们旨在确定血小板祖细胞（巨核细胞）及其周围微环境中肌营养不良聚糖（Dg）和ENaC的表达。将5周龄和28周龄自发性高血压大鼠（SHR）的骨髓薄片与年龄匹配的正常血压大鼠（WKY）进行比较。细胞计数和免疫组织化学分析表明SHR骨髓中存在氧化环境，其特征是髓过氧化物酶和3-硝基酪氨酸水平高以及过氧化物酶体增殖物激活受体II下调。此外，透射电子显微镜和共聚焦显微镜显示SHR大鼠的血小板和巨核细胞存在形态学变化，包括线粒体肿胀。定量qRT-PCR分析证实Dg mRNA下调，免疫组织化学和蛋白质印迹验证了28周龄SHR大鼠巨核细胞中β-Dg的低表达，主要是磷酸化形式。此外，与WKY对照组相比，我们观察到SHR大鼠巨核细胞中β-1整合素表达以及巨核细胞微环境中细胞外基质蛋白的逐渐增加。这些结果表明ROS的积累促进了骨髓环境中的氧化应激，并对高血压个体的细胞稳态产生不利影响。
