Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Department of Cardiology, Zhongshan Hospital, Fudan University. Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Curr Mol Med. 2018;18(10):698-710. doi: 10.2174/1566524019666190207143207.
We recently reported that Naoxintong (NXT), a China Food and Drug Administration (FDA)-approved cardiac medicine, could reduce the plaque size, but the underlying mechanism remains elusive now.
In this study, we investigated the effects of NXT on foam cell accumulation both in vivo and in vitro and explored related mechanisms.
THP-1 cells and bone marrow-derived macrophages were incubated with oxidized low-density lipoprotein (ox-LDL) with/without Naoxintong. ApoE-/- mice fed an atherogenic diet were administered to receive NXT for eight weeks. Macrophage-derived foam cell formation in plaques was measured by immunohistochemical staining. Expression of proteins was evaluated by Western blot. Lentivirus was used to knockdown PPARα in THP-1 cells.
After NXT treatment, foam cell accumulation was significantly reduced in atherosclerotic plaques. Further investigation revealed that oxidized low-density lipoprotein (ox-LDL) uptake was significantly decreased and expression of scavenger receptor class A (SR-A) and class B (SR-B and CD36) was significantly downregulated post-NXT treatment. On the other hand, NXT increased cholesterol efflux and upregulated ATP-binding cassette (ABC) transporters (ABCA-1 and ABCG-1) in macrophages. Above beneficial effects of NXT were partly abolished after lentiviral knockdown of PPARα.
Our findings suggest that NXT could retard atherosclerosis by inhibiting foam cell formation through reducing ox-LDL uptake and enhancing cholesterol efflux and above beneficial effects are partly mediated through PPARα pathway.
我们最近报道称，一种已获得中国食品药品监督管理局（FDA）批准的心脏药物脑心通（NXT）可以减少斑块大小，但目前其潜在机制尚不清楚。
在本研究中，我们研究了 NXT 对体内和体外泡沫细胞积累的影响，并探讨了相关机制。
用氧化型低密度脂蛋白（ox-LDL）孵育 THP-1 细胞和骨髓源性巨噬细胞，同时给予/不给予 NXT。载脂蛋白 E 基因敲除（ApoE-/-）小鼠给予高脂饮食，并接受 NXT 治疗 8 周。通过免疫组化染色测量斑块中巨噬细胞源性泡沫细胞的形成。通过 Western blot 评估蛋白质的表达。使用慢病毒在 THP-1 细胞中敲低过氧化物酶体增殖物激活受体α（PPARα）。
NXT 治疗后，动脉粥样硬化斑块中的泡沫细胞积累明显减少。进一步的研究表明，NXT 治疗后，氧化型低密度脂蛋白（ox-LDL）摄取明显减少，清道夫受体 A（SR-A）和 B（SR-B 和 CD36）的表达明显下调。另一方面，NXT 增加了巨噬细胞中的胆固醇流出，并上调了三磷酸腺苷结合盒（ABC）转运体（ABCA-1 和 ABCG-1）。NXT 对以上有益作用的部分作用在过氧化物酶体增殖物激活受体α（PPARα）的慢病毒敲低后被部分消除。
我们的研究结果表明，NXT 通过减少 ox-LDL 的摄取和增强胆固醇流出来抑制泡沫细胞的形成，从而延缓动脉粥样硬化的发生，上述有益作用部分通过 PPARα 途径介导。
