Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
Pharmacol Res. 2021 Jul;169:105639. doi: 10.1016/j.phrs.2021.105639. Epub 2021 Apr 28.
Atherosclerosis is now the major cause of mortality and morbidity worldwide. Formation of macrophage-derived foam cells is a hallmark of atherosclerosis, which is regulated by cholesterol uptake, intracellular metabolism, and efflux. PPARγ-LXRα-ABCA1/ABCG1 pathway plays an important part in regulating cholesterol efflux and this pathway could be a promising target for treating atherosclerosis. However, due to undesirable systemic effects, PPARγ agonist therapy for atherosclerosis remains challenging. Many traditional Chinese medicine has been well accepted and applied in atherosclerosis treatment. Yin-xing-tong-mai decoction (YXTMD) has been applied for treating atherosclerosis for decades. However, the mechanism remains to be explored. Here, we showed that YXTMD effectively attenuated atherosclerosis in ApoE mice. YXTMD increased cholesterol efflux of foam cell by upregulation of ABCA1 and ABCG1 in vivo and in vitro. Through bioinformatic analysis and experimental validation, we found that PPARγ was an important downstream effector of YXTMD in macrophages. Reduction of PPARγ significantly decreased LXRα, ABCA1, and ABCG1 expression in macrophages, with reduced cholesterol efflux. In conclusion, these findings confirmed that YXTMD attenuated atherosclerosis by activating the PPARγ-LXRα- ABCA1/ABCG1 pathway to enhance cholesterol efflux.
动脉粥样硬化现已成为全球范围内导致死亡和发病的主要原因。巨噬细胞源性泡沫细胞的形成是动脉粥样硬化的一个标志，其受胆固醇摄取、细胞内代谢和流出的调节。PPARγ-LXRα-ABCA1/ABCG1 通路在调节胆固醇流出中起着重要作用，该通路可能是治疗动脉粥样硬化的一个有前途的靶点。然而，由于全身作用不理想，PPARγ 激动剂治疗动脉粥样硬化仍然具有挑战性。许多中药在动脉粥样硬化治疗中得到了广泛的认可和应用。银杏通脉汤（YXTMD）已应用于治疗动脉粥样硬化数十年。然而，其机制仍有待探索。在这里，我们发现 YXTMD 可有效减轻 ApoE 小鼠的动脉粥样硬化。YXTMD 通过体内和体外上调 ABCA1 和 ABCG1 增加泡沫细胞的胆固醇流出。通过生物信息学分析和实验验证，我们发现 PPARγ 是 YXTMD 在巨噬细胞中的一个重要下游效应物。减少 PPARγ 会显著降低巨噬细胞中 LXRα、ABCA1 和 ABCG1 的表达，从而减少胆固醇流出。总之，这些发现证实 YXTMD 通过激活 PPARγ-LXRα-ABCA1/ABCG1 通路增强胆固醇流出来减轻动脉粥样硬化。
