Department of Pharmacy, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China.
Department of Cardiac & Thoracic Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
Mediators Inflamm. 2020 Aug 4;2020:1078365. doi: 10.1155/2020/1078365. eCollection 2020.
Oxidative stress, inflammation, and hypertension constitute a self-perpetuating vicious circle to exacerbate hypertension and subsequent hypertensive cardiac hypertrophy. NADPH oxidase (Nox) 1/4 inhibitor GKT137831 alleviates hypertensive cardiac hypertrophy in models of secondary hypertension; however, it remains unclear about its effect on hypertensive cardiac hypertrophy in models of essential hypertension. This study is aimed at determining the beneficial role of GKT137831 in hypertensive cardiac hypertrophy in spontaneously hypertensive rats (SHRs) and its mechanisms of action. Treating with GKT137831 prevented cardiac hypertrophy in SHRs. Likewise, decreasing production of reactive oxygen species (ROS) with GKT137831 reduced epidermal growth factor receptor (EGFR) activity in the left ventricle of SHRs. Additionally, EGFR inhibition also reduced ROS production in the left ventricle and blunted hypertensive cardiac hypertrophy in SHRs. Moreover, inhibition of the ROS-EGFR pathway with Nox1/4 inhibitor GKT137831 or selective EGFR inhibitor AG1478 reduced protein and mRNA levels of proinflammatory cytokines tumor necrosis factor (TNF-), interleukin 6 (IL-6), and interleukin 1 (IL-1), as well as the activities of Akt and extracellular signal-regulated kinase (ERK) 1/2 in the left ventricle of SHRs. In summary, GKT137831 prevents hypertensive cardiac hypertrophy in SHRs, Nox-deprived ROS regulated EGFR activation through positive feedback in the hypertrophic myocardium, and inhibition of the ROS-EGFR pathway mediates the protective role of GKT137831 in hypertensive cardiac hypertrophy via repressing cardiac inflammation and activation of Akt and ERK1/2. This research will provide additional details for GKT137831 to prevent hypertensive cardiac hypertrophy.
氧化应激、炎症和高血压构成了一个自我维持的恶性循环，使高血压恶化，并随后导致高血压性心肌肥厚。NADPH 氧化酶（Nox）1/4 抑制剂 GKT137831 可减轻继发性高血压模型中的高血压性心肌肥厚；然而，其在原发性高血压模型中对高血压性心肌肥厚的作用尚不清楚。本研究旨在确定 GKT137831 在自发性高血压大鼠（SHR）中的高血压性心肌肥厚中的有益作用及其作用机制。用 GKT137831 治疗可预防 SHR 中的心肌肥厚。同样，用 GKT137831 减少活性氧（ROS）的产生可降低 SHR 左心室中的表皮生长因子受体（EGFR）活性。此外，EGFR 抑制也可减少 SHR 左心室中的 ROS 产生并减弱高血压性心肌肥厚。此外，用 Nox1/4 抑制剂 GKT137831 或选择性 EGFR 抑制剂 AG1478 抑制 ROS-EGFR 通路可降低 SHR 左心室中的促炎细胞因子肿瘤坏死因子（TNF-α）、白细胞介素 6（IL-6）和白细胞介素 1（IL-1）的蛋白和 mRNA 水平，以及 Akt 和细胞外信号调节激酶（ERK）1/2 的活性。总之，GKT137831 可预防 SHR 中的高血压性心肌肥厚，Nox 剥夺的 ROS 通过肥厚心肌中的正反馈调节 EGFR 激活，并且抑制 ROS-EGFR 通路通过抑制心脏炎症和激活 Akt 和 ERK1/2 来介导 GKT137831 在高血压性心肌肥厚中的保护作用。这项研究将为 GKT137831 预防高血压性心肌肥厚提供更多细节。
