Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, PR China; Department of Pharmacology, Guangzhou Medical University, Guangzhou, Guangdong, 511436, PR China.
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, PR China.
Arch Biochem Biophys. 2018 Feb 15;640:37-46. doi: 10.1016/j.abb.2018.01.006. Epub 2018 Jan 10.
AMP-activated protein kinase (AMPK) is a central regulator of multiple metabolic pathways. It has been shown that activation of AMPK could inhibit fibroblast proliferation and extracellular matrix (ECM) accumulation, thereby suppressing cardiac fibrosis. Baicalin, the major component found in skullcap, possesses multiple protective effects on the cardiovascular system. However, little is known about the effect of baicalin on cardiac fibrosis and the molecular mechanism by which baicalin exerts its anti-fibrotic effects has not been investigated. In this study, we revealed that baicalin could inhibit cell proliferation, collagen synthesis, fibronectin (FN) and Connective tissue growth factor (CTGF) protein expression in cardiac fibroblasts induced by angiotensin Ⅱ (Ang Ⅱ). It also ameliorated cardiac fibrosis in rats submitted to abdominal aortic constriction (AAC). Moreover, baicalin inhibited transforming growth factor-β (TGF-β)/Smads signaling pathway stimulated with Ang Ⅱ through activating AMPK. Subsequently, we also demonstrated that baicalin attenuated Ang Ⅱ-induced Smad3 nuclear translocation, and interaction with transcriptional coactivator p300, but promoted the interaction of p300 and AMPK. Taken together, these results provide the first evidence that the effect of baicalin against cardiac fibrosis may be attributed to its regulation on AMPK/TGF-β/Smads signaling, suggesting the therapeutic potential of baicalin on the prevention of cardiac fibrosis and heart failure.
AMP 激活的蛋白激酶 (AMPK) 是多种代谢途径的核心调节剂。研究表明，激活 AMPK 可以抑制成纤维细胞增殖和细胞外基质 (ECM) 积累，从而抑制心肌纤维化。黄芩苷是黄芩的主要成分，对心血管系统具有多种保护作用。然而，关于黄芩苷对心肌纤维化的影响知之甚少，也尚未研究黄芩苷发挥抗纤维化作用的分子机制。在本研究中，我们揭示了黄芩苷可以抑制血管紧张素Ⅱ (Ang Ⅱ) 诱导的心肌成纤维细胞增殖、胶原合成、纤连蛋白 (FN) 和结缔组织生长因子 (CTGF) 蛋白表达，同时改善腹主动脉缩窄 (AAC) 大鼠的心肌纤维化。此外，黄芩苷通过激活 AMPK 抑制 Ang Ⅱ刺激的转化生长因子-β (TGF-β)/Smads 信号通路。随后，我们还证明黄芩苷抑制了 Ang Ⅱ诱导的 Smad3 核转位，并抑制了转录共激活因子 p300 与 Smad3 的相互作用，但促进了 p300 与 AMPK 的相互作用。综上所述，这些结果首次提供了证据表明，黄芩苷抗心肌纤维化的作用可能归因于其对 AMPK/TGF-β/Smads 信号通路的调节，提示黄芩苷在预防心肌纤维化和心力衰竭方面具有治疗潜力。
