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. 2017 Jul 7;8(47):82196-82206.
doi: 10.18632/oncotarget.19072. eCollection 2017 Oct 10.

QiShenYiQi pill attenuates atherosclerosis by promoting regulatory T cells, inhibiting T helper 17 cells and accelerating cholesterol excretion

Li Peng  1 , Chong-Shan Lv  1 , Yun Zhao  1 , Shao-Dong Chen  1 , Yang Huang  1 , Da-Wei Lu  1 , Shu-Qiong Huang  1 , Zong-Bao Yang  1 , Lin-Chao Qian  1 , Lei Wen  1
Affiliations

QiShenYiQi pill attenuates atherosclerosis by promoting regulatory T cells, inhibiting T helper 17 cells and accelerating cholesterol excretion

Li Peng et al. Oncotarget. .

Abstract

Objective: The aim of this study was to explore potential immunoregulatory mechanisms underlying the suppressive effect on atherosclerosis of QiShenYiQi pill (QSYQ).

Methods and results: Male ApoE-/- mice were maintained on a Western-type diet and QSYQ treatment for eight weeks. Determination of atherosclerosis demonstrated that QSYQ attenuated plaque formation and decreased the level of blood low-density lipoproteins-cholesterol. QSYQ treatment did not affect body weight but reduced the ratio of liver weight and body weight. Western blots of liver showed that QSYQ increased the expression of liver X receptor alpha and ATP-binding cassette sub-family G member 5. Western blots of atherosclerotic aorta revealed that QSYQ inhibited the expression of cluster of differentiation 36, promoted the expression of forkhead box P3 and decreased interleukin-17A expression. Western blots of spleen showed that QSYQ decreased the expression of mothers against decapentaplegic homolog 2/3 and forkhead box P3, as well as attenuated the expression of spleen interleukin-6, RAR-related orphan receptor gamma and interleukin-17A.

Conclusions: QSYQ exerted an anti-atherosclerosis effect by promoting regulatory T cells in atherosclerotic lesion, inhibiting T helper 17 cells in plaque and spleen and accelerating liver cholesterol excretion.

Keywords: QiShenYiQi; atherosclerosis; cholesterol excretion; interleukin-17; regulatory T cell.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1. Effect of QSYQ on atherosclerotic lesion and blood lipids in ApoE-/- mice
(A) Representative photomicrographs of Sudan IV staining in aortic root of male ApoE-/- mice treated with QSYQ or control saline. (B and C) The quantitative comparison of atherosclerotic lesion size and relative lesion area between drug treatment groups and model group (n=6). (D and E) The serum TC and LDL-C of ApoE-/- mice were detected and compared between drug treatment groups and model group (n=6). Data were showed as mean ± standard deviation and compared by one-way analysis of variance and following with Fisher’s Least Significant Difference test for individual comparisons. n.s.p > 0.05; ★p < 0.05; ★★p < 0.01.
Figure 2
Figure 2. Effect of QSYQ on liver weight and liver cholesterol excretion pathway of ApoE-/- mice
(A and B) After eight weeks western-type diet and QSYQ treatment, the body weight and the ratio of liver weight versus body weight of ApoE-/- mice were recorded and compared between drug treatment groups and model group (n=6). (C) The expression of LDLR, LXR-αand ABCG5 in liver of ApoE-/- mice were detected by western blotting. (D, E and F) The quantitative comparison of LDLR, LXR-αand ABCG5 between drug treatment groups and model group (n=3). Data were showed as mean ± standard deviation and compared by one-way analysis of variance and following with Fisher’s Least Significant Difference test for individual comparisons. n.s.p > 0.05; ★p < 0.05; ★★p < 0.01.
Figure 3
Figure 3. Effect of QSYQ on regulatory T cells and T helper 17 cells in atherosclerotic aorta of ApoE-/- mice
(A) The expression of CD36 (macrophage-related), TGF-β1/Foxp3 (regulatory T cells-related) and RORγ/IL-17A (T helper 17 cells-related) in atherosclerotic aorta of ApoE-/- mice were detected by western blotting. (B, C, D, E and F) The quantitative comparison of CD36, TGF-β1, Foxp3, RORγ and IL-17A between drug treatment groups and model group (n=3). Data were showed as mean ± standard deviation and compared by one-way analysis of variance and following with Fisher’s Least Significant Difference test for individual comparisons. n.s.p > 0.05; ★p < 0.05.
Figure 4
Figure 4. Effect of QSYQ on regulatory T cells and T helper 17 cells in spleen of ApoE-/- mice
(A) The expression of TGF-β1/Smad2/3/Foxp3 (regulatory T cells-related) and IL-6/RORγ/IL-17A (T helper 17 cells-related) in spleen of ApoE-/- mice were detected by western blotting. (B, C, D, E, F and G) The quantitative comparison of TGF-β1, Smad2/3, Foxp3, IL-6, RORγ and IL-17A between drug treatment groups and model group (n=3). Data were showed as mean ± standard deviation and compared by one-way analysis of variance and following with Fisher’s Least Significant Difference test for individual comparisons. n.s.p > 0.05; ★p < 0.05.
Figure 5
Figure 5. Proposed mechanism underlying QSYQ against atherosclerosis
During the development of atherosclerosis, macrophages roll and adhere on the injured endothelium and then infiltrate into sub-endothelium. Macrophages phagocytize oxidized LDL-C and turn into foam cell, which deposit in the sub-endothelium and form the lipid core of atherosclerotic plaque. Treg (Foxp3+) and Th17 (RORγt+) in spleen immigrate into plaque area. IL-17, the major pro-inflammatory cytokine secreted by Th17 in spleen and atherosclerotic plaque, promotes the rolling and adhering of macrophage, which can be inhibited by TGF-β1. In addition, blood LDL is combined by LDLR of hepatocyte and excreted into bile by LXR-α and ABCG5. The mechanism of QSYQ inhibiting atherosclerosis include promoting Treg immigration into atherosclerotic plaque, inhibiting the secretion of IL17 by Th17 in spleen and plaque, blocking oxidized LDL phagocytized by macrophage through CD36, and increasing the expression of LXR-α and ABCG5 in liver. Notes: QSYQ means QiShenYiQi pill, Treg means regulatory T cell, Th17 means T helper 17 cell, Foxp3 means forkhead box P3, RORγt means RAR-related orphan receptor gamma t, IL-17 means interleukin-17, TGF-β1 means transforming growth factor beta 1, CD36 means cluster of differentiation 36, LDL means low-density lipoproteins, LDLR means LDL receptor, LXR-α means liver X receptor alpha, ABCG5 means ATP-binding cassette sub-family G member 5, Black arrow means promotion or movement, T-type line means inhibition.
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