Key Laboratory of Medical Electrophysiology of the Ministry of Education and Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.
Department of Cardiology, Southwest Medical University, Luzhou, China.
Gerontology. 2023;69(9):1076-1094. doi: 10.1159/000531596. Epub 2023 Jun 22.
Attenuating cardiac fibroblasts activation contributes to reducing excessive extracellular matrix deposition and cardiac structural remodeling in hypertensive hearts. Acacetin plays a protective role in doxorubicin-induced cardiomyopathy and ischemia/reperfusion injury. The aim of this study was to investigate the potential molecular mechanisms underlying the protective role of acacetin on hypertension-induced cardiac fibrosis.
Echocardiography, histopathological methods, and Western blotting techniques were used to evaluate the anti-fibrosis effects in spontaneous hypertensive rat (SHR) which were daily intragastrically administrated with acacetin (10 mg/kg and 20 mg/kg) for 6 weeks. Angiotensin II (Ang II) was used to induce cellular fibrosis in human cardiac fibroblasts (HCFs) in the absence and presence of acacetin treatment for 48 h.
Acacetin significantly alleviated hypertension-induced increase in left ventricular (LV) posterior wall thickness and LV mass index in SHR. The expressions of collagen-1, collagen-III, and alpha-smooth muscle actin (α-SMA) were remarkedly decreased after treatment with acacetin (n = 6, p < 0.05). In cultured HCFs, acacetin significantly attenuated Ang II-induced migration and proliferation (n = 6, p < 0.05). Moreover, acacetin substantially inhibited Ang II-induced upregulation of collagen-1 and collagen-III (n = 6, p < 0.05) and downregulated the expression of alpha-SMA in HCFs. Additionally, acacetin decreased the expression of TGF-β1, p-Smad3/Smad3, and p-AKT and p-mTOR but increased the expression of Smad7 (n = 6, p < 0.05). Further studies found that acacetin inhibited TGF-β1 agonist SRI and AKT agonist SC79 caused fibrotic effect.
Acacetin inhibits the hypertension-associated cardiac fibrotic processes through regulating TGF-β/Smad3, AKT/mTOR signal transduction pathways.
抑制心肌成纤维细胞的激活有助于减少高血压心脏中外源性细胞外基质的沉积和心脏结构的重塑。阿克替宁可在阿霉素诱导的心肌病和缺血再灌注损伤中发挥保护作用。本研究旨在探讨阿克替宁对高血压诱导的心脏纤维化的保护作用的潜在分子机制。
通过超声心动图、组织病理学方法和 Western blot 技术评估自发性高血压大鼠（SHR）经阿克替宁（10 mg/kg 和 20 mg/kg）灌胃 6 周后的抗纤维化作用。在不存在和存在阿克替宁处理的情况下，用血管紧张素 II（Ang II）诱导人心脏成纤维细胞（HCFs）发生细胞纤维化 48 小时。
阿克替宁可显著减轻 SHR 高血压引起的左心室（LV）后壁厚度和 LV 质量指数增加。用阿克替宁处理后，胶原-1、胶原-III 和 α-平滑肌肌动蛋白（α-SMA）的表达明显降低（n = 6，p < 0.05）。在培养的 HCFs 中，阿克替宁显著抑制 Ang II 诱导的迁移和增殖（n = 6，p < 0.05）。此外，阿克替宁还可显著抑制 Ang II 诱导的胶原-1 和胶原-III 的上调（n = 6，p < 0.05）和 HCFs 中α-SMA 的表达下调。此外，阿克替宁降低了 TGF-β1、p-Smad3/Smad3 和 p-AKT、p-mTOR 的表达，但增加了 Smad7 的表达（n = 6，p < 0.05）。进一步研究发现，阿克替宁抑制 TGF-β1 激动剂 SRI 和 AKT 激动剂 SC79 引起的纤维化作用。
阿克替宁通过调节 TGF-β/Smad3、AKT/mTOR 信号转导通路抑制与高血压相关的心脏纤维化过程。
