Resveratrol prevents ISO-induced myocardial remodeling associated with regulating polarization of macrophages through VEGF-B/AMPK/NF-kB pathway
Resveratrol prevents ISO-induced myocardial remodeling associated with regulating polarization of macrophages through VEGF-B/AMPK/NF-kB pathway
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白藜芦醇预防 ISO 诱导的心肌重塑，该重塑与通过 VEGF-B/AMPK/NF-kB 途径调节巨噬细胞极化相关
DOI：
10.1016/j.intimp.2020.106508
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发表时间：
2020-07-01
影响因子：
5.6
通讯作者：
Qi, Zhi
中科院分区：
文献类型：
--
作者：
Li, Yafei;Feng, Lifeng;Qi, Zhi
巨噬细胞扩增和炎症反应参与诱导心脏重塑。白藜芦醇具有很强的抗炎作用，但其对巨噬细胞浸润和极化的影响尚不清楚。本研究旨在探讨呼吸道合胞病毒（RSV）对异丙肾上腺素（ISO）诱导的小鼠心肌重构的抗炎作用及其对巨噬细胞极化的调节作用。BALB/c小鼠每天口服RSV（100 mg/kg）一周，然后每天皮下注射ISO（50 mg/kg）一周。对小鼠注射ISO引起心脏功能障碍，表现为心脏肥大和心肌细胞纤维化。同时，在ISO处理的小鼠中发现巨噬细胞M1极化，这通过心脏中Ly 6C（低）巨噬细胞百分比、M1细胞因子水平和CD 68表达的增加以及Ly 6C（高）巨噬细胞百分比、M2细胞因子水平和CD 206表达的降低来证明。当小鼠用RSV预处理时，心脏和巨噬细胞M1极化的所有这些变化都得到改善。还在RAW 264.7细胞中测试了RSV对巨噬细胞极化的影响。发现用RSV预处理降低ISO处理的细胞中M1标志物或促炎细胞因子的水平，而增加M2标志物的水平。另外，RSV可上调RAW 264. 7细胞和小鼠的VEGF-B表达和AMPK活性，下调NF-κ B p65磷酸化表达。此外，VEGF-B siRNA预处理大大逆转了RSV在RAW 264. 7细胞中引起的几乎所有上述参数的变化。RSV可能通过抑制VEGFB/AMPK/NF-κ B B途径抑制巨噬细胞的M1极化，从而对ISO诱导的心肌损伤具有潜在的治疗作用。
Macrophage expansion and inflammatory responses are involved in induction of cardiac remodeling. Resveratrol has strong anti-inflammatory effects, however its effect on macrophage infiltration and polarization is unknown. This study aimed to investigate the anti-inflammatory effects of RSV on ISO-induced myocardial remodeling in mice and its regulatory role in macrophage polarization. BALB/c mice were orally administered with RSV (100 mg/kg) daily for one week, then were subcutaneously injected with ISO (50 mg/kg) daily for another week. ISO injections to mouse caused cardiac dysfunction evidenced by cardiac hypertrophy and cardiomyocyte fibrosis. Meanwhile, macrophage M1 polarization was found in ISO treated mice, which was evidenced by increased percentage of Ly6C(low) macrophages in the heart, levels of M1 cytokines and expression of CD68, and decreased percentage of Ly6C(high) macrophage, levels of M2 cytokines and expression of CD206. All these changes in cardiac and macrophage M1 polarization were ameliorated when mice were pretreated with RSV. The effect of RSV on macrophage polarization was also tested in RAW264.7 cells. It was found that pre-treatment with RSV decreased the levels of M1 marker or proinflammatory cytokines, while increased the levels of M2 markers in ISO treated cells. In addition, it was found that RSV could upregulate the expression of VEGF-B and the activity of AMPK, while it downregulated the expression of phosphorylated NF-kappa B p65 both in RAW264.7 cells and in mice. Furthermore, pretreatment with VEGF-B siRNA greatly reversed changes in almost all above parameters evoked by RSV in RAW264.7 cells. Therefore, our findings suggest RSV has potential therapeutic effects in ISO-induced myocardial injury, which may be by inhibiting the M1 polarization of macrophages through VEGFB/AMPK/NF-kappa B pathway.