Department of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Clin Sci (Lond). 2018 Aug 30;132(16):1837-1853. doi: 10.1042/CS20180312. Print 2018 Aug 31.
Rho-kinase has relevant functions in blood pressure modulation and cardiovascular remodeling. Rho-kinase activity is determined in circulating leukocytes measuring phosphorylation of its target myosin phosphatase target subunit 1 (MYPT1), but its relationship with Rho-kinase activity in the myocardium and in vasculature in hypertension has not been evaluated.The aim was to determine the degree of association between Rho-kinase cascade activation in circulating leukocytes with cardiac and aortic Rho-kinase pathway activation in a model of hypertension and to analyze it with a cause-effect perspective.Hypertensive deoxycorticosterone (DOCA)-salt rats received the Rho-kinase antagonist fasudil (DOCA-Fas, 100 mg/kg/day, 3 weeks). Results were compared with an untreated DOCA-salt and a sham group.Rho-kinase inhibition reduced significantly blood pressure, cardiac hypertrophy, myocardial collagen and macrophage infiltration, but not aortic wall hypertrophy. Fasudil decreased significantly Rho-kinase activity in peripheral blood mononucleated cells (PBMC), myocardium and aortic wall to similar levels as in the sham group. A significant correlation was found between PBMC Rho-kinase activity and cardiac remodeling, specifically with hypertrophy ( = 0.51, ≤0.01), myocardial collagen ( = 0.40, ≤0.05) and ED1 immunostaining ( = 0.48, ≤0.01). In the untreated hypertensive group, increased levels (<0.05) of the proinflammatory molecules p65 NF-κB, vascular cell adhesion molecule 1 and interleukin-6 antibody in the myocardium, aortic wall and PBMC were observed and were reduced with fasudil (<0.05).In conclusion, in this hypertension model, Rho-kinase and its pathway activation determined in circulating leukocytes reflect the activation of this pathway in the myocardium and in the aortic wall and are significantly related to myocardial remodeling (hypertrophy, fibrosis and inflammation).
Rho-kinase 在血压调节和心血管重塑中具有相关功能。通过测量其靶标肌球蛋白磷酸酶靶亚单位 1（MYPT1）的磷酸化来确定循环白细胞中的 Rho-kinase 活性，但其与高血压中心肌和血管中的 Rho-kinase 活性之间的关系尚未得到评估。目的是确定循环白细胞中 Rho-kinase 级联激活与高血压模型中心脏和主动脉 Rho-kinase 途径激活之间的关联程度，并从因果关系的角度进行分析。给予高血压脱氧皮质酮（DOCA）-盐大鼠 Rho-kinase 拮抗剂法舒地尔（DOCA-Fas，100mg/kg/天，3 周）。将结果与未经处理的 DOCA-盐组和假手术组进行比较。Rho-kinase 抑制显著降低了血压、心脏肥大、心肌胶原和巨噬细胞浸润，但不降低主动脉壁肥大。法舒地尔显著降低了外周血单核细胞（PBMC）、心肌和主动脉壁中的 Rho-kinase 活性，使其与假手术组相似。发现 PBMC Rho-kinase 活性与心脏重塑，特别是与肥大（ = 0.51，≤0.01）、心肌胶原（ = 0.40，≤0.05）和 ED1 免疫染色（ = 0.48，≤0.01）之间存在显著相关性。在未经处理的高血压组中，观察到心肌、主动脉壁和 PBMC 中促炎分子 p65 NF-κB、血管细胞黏附分子 1 和白细胞介素-6 抗体的水平升高（<0.05），并用法舒地尔降低（<0.05）。结论，在该高血压模型中，循环白细胞中确定的 Rho-kinase 及其途径激活反映了该途径在心肌和主动脉壁中的激活，并与心肌重塑（肥大、纤维化和炎症）显著相关。
