Department of Physiology, School of Basic Medical Science, North China University of Science and Technology, No. 57, Jianshe South Road, Tangshan, 063000, Hebei Province, People's Republic of China.
Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, North China University of Science and Technology, Tangshan, Hebei Province, People's Republic of China.
Pflugers Arch. 2017 Sep;469(9):1061-1071. doi: 10.1007/s00424-017-1984-0. Epub 2017 Apr 28.
The intermediate-conductance Ca-activated K (K3.1) channels play a pivotal role in the cardiac fibroblast proliferation and inflammatory reaction during the progression of myocardial fibrosis. However, the relationship between K3.1 expression and oxidative stress, the important factor of promoting fibrosis, has not been clearly established. This study was designed to investigate whether the role of oxidative stress in promoting myocardial fibrosis is related to K3.1 channel by using biochemical approaches. It was found that mean blood pressure, plasma Ang II level, and myocardium malondialdehyde (MDA) content of angiotensinogen-renin (AGT-REN) double transgenic hypertension (dTH) mice were higher than those in wild-type (WT) mice of the same age (4, 8 and 12 months) and were significantly increased with age. However, plasma Ang (1-7) level and myocardium superoxide dismutase (SOD) activity showed a downward trend and were lower than those of the same-aged WT mice (4, 8 and 12 months). In addition, protein expression of myocardium K3.1 channel in 4-, 8-, and 12-month-old dTH mice were significantly higher than that of the same-aged WT mice and gradually increased with age. TRAM-34, a blocker of K3.1 channel, and losartan mitigated the myocardial structural and functional damage by inhibiting collagen deposition and decreasing the expression of β-MHC. After intervention of ROS scavenger N-acetyl cysteine (NAC) and NADPH inhibitor apocynin (Apo) in 6-month-old dTH mice for 4 weeks, myocardial oxidative stress level was reduced and K3.1 channel protein expression was decreased. Meanwhile, Apo inhibited the myocardium p-ERK1/2/T-ERK protein expression in dTH mice, and after blockage of ERK1/2 pathway with PD98059, the K3.1 protein expression was reduced. These results demonstrate for the first time that K3.1 channel is likely to be a critical target on the oxidative stress for its promoting role in myocardial fibrosis, and the ERK1/2 pathway may be involved in the regulation of oxidative stress to K3.1.
中等电导钙激活钾（K3.1）通道在心肌纤维化进展过程中心肌成纤维细胞增殖和炎症反应中起关键作用。然而，K3.1 表达与氧化应激（促进纤维化的重要因素）之间的关系尚未明确确立。本研究旨在通过生化方法研究氧化应激在促进心肌纤维化中的作用是否与 K3.1 通道有关。研究发现，血管紧张素原-肾素（AGT-REN）双转基因高血压（dTH）小鼠的平均血压、血浆血管紧张素 II（Ang II）水平和心肌丙二醛（MDA）含量高于同年龄的野生型（WT）小鼠（4、8 和 12 个月），且随年龄增长而显著升高。然而，血浆 Ang（1-7）水平和心肌超氧化物歧化酶（SOD）活性呈下降趋势，低于同年龄 WT 小鼠（4、8 和 12 个月）。此外，4、8 和 12 个月龄 dTH 小鼠心肌 K3.1 通道蛋白表达明显高于同年龄 WT 小鼠，且随年龄增长逐渐升高。K3.1 通道阻滞剂 TRAM-34 和氯沙坦通过抑制胶原沉积和降低β-MHC 的表达减轻心肌结构和功能损伤。在 6 月龄 dTH 小鼠中用 ROS 清除剂 N-乙酰半胱氨酸（NAC）和 NADPH 抑制剂 apocynin（Apo）干预 4 周后，心肌氧化应激水平降低，K3.1 通道蛋白表达减少。同时，Apo 抑制 dTH 小鼠心肌 p-ERK1/2/T-ERK 蛋白表达，用 PD98059 阻断 ERK1/2 通路后，K3.1 蛋白表达减少。这些结果首次表明，K3.1 通道可能是氧化应激促进心肌纤维化的关键靶点，ERK1/2 通路可能参与调节氧化应激对 K3.1 的作用。
