Berberine Inhibits Oxygen Consumption Rate Independent of Alteration in Cardiolipin Levels in H9c2 Cells
Berberine Inhibits Oxygen Consumption Rate Independent of Alteration in Cardiolipin Levels in H9c2 Cells
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DOI：
10.1007/s11745-017-4300-z
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发表时间：
2017-09
期刊：
影响因子：
1.9
通讯作者：
Wenguang Chang;Ming Zhang;Li Chen;G. Hatch
中科院分区：
文献类型：
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作者：
Wenguang Chang;Ming Zhang;Li Chen;G. Hatch
小型临床研究表明，口服植物生物碱小檗碱（BBR）降低血糖水平与二甲双胍相似，并促进其作为一种新型抗糖尿病治疗方法的使用。然而，体外研究表明，高浓度的BBR通过抑制线粒体功能有效地抑制细胞增殖。心磷脂（Ptd2Gro）是调节线粒体生物能量功能所需的关键磷脂。我们研究了BBR是否通过改变Ptd2Gro代谢来抑制H9c2心肌细胞的耗氧率。用海马XF24分析仪测定，用BBR处理H9c2细胞导致氧耗率（OCR）迅速（在几分钟内）浓度依赖性下降。低至1µM的BBR对OCR的抑制效果较好。此外，在未处理的细胞中观察到，所有浓度的BBR都抑制脂肪酸介导的OCR增加。用25µM BBR处理H9c2细胞24小时可显著减少[3H]胸腺嘧啶掺入细胞，但不改变Ptd2Gro池的大小。相比之下，12.5µM BBR增加了[1-14C]棕榈酸酯向Ptd2Gro的掺入，12.5µM和25µM BBR减少了[1-14C]油酸酯向Ptd2Gro的掺入。已知蛋白激酶Cδ (PKCδ)通过其增加的膜关联激活可以改变Ptd2Gro在线粒体内的分布。BBR处理导致膜相关PKCδ减少，减弱棕榈酸盐介导的PKCδ膜相关增加。因此，BBR治疗H9c2心肌细胞可抑制细胞OCR，而不依赖于Ptd2Gro水平的改变。
Small clinical studies have shown that oral treatment with the plant alkaloid berberine (BBR) reduces blood glucose levels similar to that of metformin and have promoted its use as a novel anti-diabetic therapy. However,in vitrostudies have shown that high concentrations of BBR potently inhibit cell proliferation through inhibition of mitochondrial function. Cardiolipin (Ptd2Gro) is a key phospholipid required for regulating mitochondrial bioenergetic function. We examined if BBR inhibited oxygen consumption rate in H9c2 cardiac myocytes through alteration in Ptd2Gro metabolism. Treatment of H9c2 cells with BBR resulted in a rapid (within minutes) concentration-dependent decrease in the oxygen consumption rate (OCR) as determined using a Seahorse XF24 analyzer. Concentrations of BBR as low as 1 µM were effective in inhibiting OCR. In addition, all concentrations of BBR inhibited the fatty acid-mediated increase in OCR that was observed in untreated cells. Treatment of H9c2 cells with up to 25 µM BBR for 24 h markedly reduced [3H]thymidine incorporation into cells but did not alter the pool size of Ptd2Gro. In contrast, 12.5 µM BBR increased [1-14C]palmitate incorporation into Ptd2Gro and 12.5 µM and 25 µM BBR reduced [1-14C]oleate incorporation into Ptd2Gro. Protein kinase C delta (PKCδ) activation through its increased membrane association is known to alter Ptd2Gro distribution within mitochondria. BBR treatment resulted in a decrease in membrane-associated PKCδ and attenuated the palmitate-mediated increase in PKCδ membrane-association. Thus, BBR treatment of H9c2 cardiac myocytes inhibits cellular OCR independent of alteration in Ptd2Gro levels.