Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China.
Department of Pediatrics, Case Western Reserve University School of Medicine, UH Rainbow Babies and Children's Hospital, Cleveland, OH, 44106, USA.
J Ethnopharmacol. 2020 Aug 10;258:112767. doi: 10.1016/j.jep.2020.112767. Epub 2020 Mar 19.
The abnormal increase in vascular smooth muscle cell (VSMC) proliferation is widely accepted as the pivotal process in the vascular remodeling of hypertension. Qingda granule (QDG) is simplified from Qingxuan Jiangya Decoction (QXJYD) which has been in usage for a long time as a traditional Chinese medicine formula to treat hypertension based on the theory of traditional Chinese medicine. However, its underlying molecular mechanisms of action remain largely unknown.
To investigate the therapeutic efficacy of QDG in the attenuation of elevation of blood pressure and proliferation of VSMCs in vivo and in vitro and explore its possible mechanism of action.
In vivo, we established an angiotensin Ⅱ (Ang Ⅱ)-mediated hypertension model in C57BL/6 mice and orally administered 1.145 g/kg/day of QDG. The systolic and diastolic blood pressures of all mice were measured at the end of the treatment by using the tail-cuff plethysmograph method and CODA™ noninvasive blood pressure system. VSMC proliferation within the aorta was determined by immunohistochemistry. In vitro, primary rat VSMCs were cultured to further verify the effects of QDG on Ang Ⅱ induced VSMC proliferation. Cell proliferation was investigated using cell counting and MTT assays. The protein expression was determined by western blotting.
We found that oral administration of QDG significantly attenuated the elevation of blood pressure and proliferation of VSMCs in Ang Ⅱ-induced hypertensive mice. Moreover, QDG remarkably inhibited Ang Ⅱ-induced primary rat VSMCs proliferation and decreased mitogen-activated protein kinase (MAPK) and PI3K/AKT activity by attenuating the expression of phospho-extracellular signaling-regulated kinase 1/2, phospho-p38, phospho-c-Jun N-terminal kinase and phospho-protein kinase B.
Collectively, our findings suggest that QDG attenuates Ang Ⅱ-induced elevation of blood pressure and proliferation of VSMCs through a decrease in the activation of MAPK and PI3K/AKT pathways. Based on this study, we postulate this could be one of the mechanisms whereby QDG effectively controls hypertension.
血管平滑肌细胞（VSMC）增殖异常被广泛认为是高血压血管重构的关键过程。清达颗粒（QDG）是从长期以来用于治疗高血压的中药方剂——清眩降压汤（QXJYD）简化而来的。然而，其作用的潜在分子机制在很大程度上仍然未知。
研究 QDG 对体内和体外血压升高和 VSMC 增殖的抑制作用，并探讨其可能的作用机制。
在体内，我们建立了血管紧张素Ⅱ（Ang Ⅱ）介导的高血压模型，并用 QDG 进行口服治疗，剂量为 1.145 g/kg/天。在治疗结束时，使用尾套测压法和 CODA™无创血压系统测量所有小鼠的收缩压和舒张压。通过免疫组织化学法测定主动脉内的 VSMC 增殖。在体外，培养原代大鼠 VSMC 进一步验证 QDG 对 Ang Ⅱ诱导的 VSMC 增殖的影响。使用细胞计数和 MTT 测定法研究细胞增殖。通过 Western blot 测定蛋白表达。
我们发现，QDG 的口服给药可显著减轻 Ang Ⅱ诱导的高血压小鼠血压升高和 VSMC 增殖。此外，QDG 可显著抑制 Ang Ⅱ诱导的原代大鼠 VSMC 增殖，并通过降低丝裂原活化蛋白激酶（MAPK）和 PI3K/AKT 活性来降低磷酸化细胞外信号调节激酶 1/2、磷酸化 p38、磷酸化 c-Jun N 端激酶和磷酸化蛋白激酶 B 的表达。
综上所述，我们的研究结果表明，QDG 通过降低 MAPK 和 PI3K/AKT 通路的激活来减轻 Ang Ⅱ诱导的血压升高和 VSMC 增殖。基于这项研究，我们推测这可能是 QDG 有效控制高血压的机制之一。
