PPAR-γ激动剂吡格列酮抑制血管紧张素Ⅱ诱导树突状细胞免疫激活致动脉粥样硬化斑块不稳定的研究
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摘要
体外研究：PPAR-γ激动剂吡格列酮抑制外源性血管紧张素Ⅱ诱导树突状细胞功能活化及其信号转导机制
目的：肾素血管紧张素系统在树突状细胞(dendritic cell, DC)上表达并具有功能活性,提示血管紧张素Ⅱ(angiotensinⅡ, AngⅡ)可能通过调节DC功能在免疫炎症反应过程中发挥重要的作用。本部分体外研究过氧化物酶体增生物激活受体-γ(peroxisome protiferator activated receptor-gamma, PPAR-γ)激动剂吡格列酮(pioglitazone, Pio)对外源性AngⅡI诱导DC功能活化的影响,并进一步探讨其内在的信号转导机制。
方法：体外分离培养人外周血单核细胞来源的DC,直接加入AngⅡ干预,或者经PPAR-γ激动剂Pio预处理后再加入AngⅡ干预。然后采用流式细胞学技术检测DC表达表型分子CD80、CD86、CD83和HLA-DR的功能,酶联免疫吸附试验检测DC分泌细胞因子IL-6、TNF-α和IL-12的功能,混合淋巴细胞反应检测DC刺激T淋巴细胞增殖的功能。进一步通过蛋白印迹试验检测DC内丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)的磷酸化,电泳迁移率转变试验检测DC内核因子-κB(nuclear factor kappa B, NF-κB)的活性。
结果：外源性AngⅡ的刺激能上调人单核细胞来源DC表面的成熟标记分子CD83和共刺激分子CD86,但对共刺激分子CD80和MHC-II类分子HLA-DR的表达无显著影响；能促进DC分泌炎症因子IL-6和TNF-a,但对T淋巴细胞刺激因子IL-12分泌的促进作用不明显；能显著增强成熟DC刺激的T淋巴细胞增殖反应,但对未成熟DC刺激T淋巴细胞增值能力的增加不明显。经PPAR-γ激动剂Pio预处理能明显抑制AngⅡ诱导DC上调CD83分子表达,但对AngⅡ上调CD86分子表达无显著影响；能减少Ang II促进DC分泌IL-12和TNF-a,但对Ang II刺激IL-6分泌影响不大；Pio还能够阻断Ang II协同刺激DC激活T淋巴细胞增殖反应。进一步研究发现,外源性AngⅡ刺激人单核细胞来源DC能促进DC内细胞外信号调节激酶(extracellular signal-related kinase, ERK)和P38 MAPK的磷酸化,但对c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)磷酸化的作用不明显；还能增强DC内NF-κB/DNA结合活性。经PPAR-y激动剂Pio预处理能明显抑制AngⅡ促进DC内ERK和P38 MAPK的磷酸化,而且还能降低AngⅡ增强的DC内NF-κB/DNA结合活性。
总结：PPAR-γ激动剂Pio能抑制外源性AngⅡ诱导DC功能活化,其内在的分子机制至少部分是通过阻断MAPK和NF-κB信号转导通路实现的。这些研究的发现进一步证实了上述多种介质相互作用在调节DC介导的免疫炎症过程中具有十分重要的作用。
体内研究：PPAR-y激动剂吡格列酮抑制内源性血管紧张素Ⅱ致ApoE基因缺陷小鼠动脉粥样硬化斑块不稳定及其免疫炎症机制
目的：动脉粥样硬化易损斑块破裂是引起急性心血管事件的主要原因,但是导致斑块失稳的具体机制至今仍未完全阐明。在前面的体外研究中我们已经发现PPAR-γ激动剂Pio能抑制外源性AngⅡ诱导DC功能活化,本部分实验通过建立内源性高AngⅡ动脉粥样硬化小鼠模型,研究在体情况下PPAR-γ激动剂Pio对内源性Ang II诱导ApoE-/-小鼠动脉粥样硬化斑块不稳定的影响,并进一步探讨DC介导的免疫炎症机制在动脉粥样硬化斑块易损中的作用。
方法：在Apo-/-小鼠的基础上进行两肾一夹(two kidney one clip,2K1C)手术,建立内源性高AngⅡ动脉粥样硬化小鼠模型,另行假手术作为对照。2K1C术后小鼠分成两组,其中一组予PPAR-y激动剂Pio 20 mg/kg/d灌胃,称为2K1C+Pio组,另一组予等量生理盐水灌胃,称为2K1C组；假手术小鼠也分成两组,其中一组予Pio 20 mg/kg/d灌胃,称为sham+Pio组,另一组予等量生理盐水灌胃,称为sham组。各组小鼠严格按照实验计划连续处理12周,然后经有创颈动脉测压法测定动脉血压,常规生化检测血脂、血糖水平,放射免疫法检测血浆肾素活性和Ang II浓度；主动脉弓大体照片和胸腹主动脉油红O染色观测主动脉斑块负荷,主动脉根部组织切片苏木精-伊红染色和平滑肌细胞肌动蛋白免疫组化染色评价斑块易损性,CD3免疫组化染色T淋巴细胞,S-100蛋白和C-C家族趋化因子受体-7(C-C chemokine receptor type 7, CCR7)免疫组化双染色DC检测斑块内免疫炎症细胞的浸润及功能状态。
结果：成功建立内源性高Ang II动脉粥样硬化小鼠模型,2K1C术后ApoE-/-小鼠动脉血压显著增高,血浆肾素活性明显增强,Ang II浓度显著增高；Pio药物干预以后ApoE-/-小鼠动脉血压无明显变化,虽然血浆肾素活性增强,但Ang II浓度未见明显差异；2K1C术后和Pio药物干预对ApoE-/-小鼠体重、心率,血脂、血糖水平均无明显影响。2K1C术后所致的内源性高Ang II能促进ApoE-/-小鼠动脉粥样硬化发展：主动脉弓和胸腹主动脉的斑块负荷增加,斑块面积增大；还能促进斑块易损性：斑块脂质核心增大,纤维帽变薄甚至破坏,斑块内平滑肌细胞含量减少,T淋巴细胞浸润增加。Pio药物治疗能延缓内源性Ang II所致的ApoE-/-小鼠动脉粥样硬化进展：主动脉弓和胸腹主动脉的斑块负荷降低,斑块面积减少；还能抑制斑块的易损性：脂质核心减小,纤维帽增厚并且连续完整,斑块内平滑肌细胞含量增加,T淋巴细胞浸润减少。进一步研究发现,2K1C术后所致的内源性高Ang II能促进ApoE-/-小鼠动脉粥样硬化斑块内DC浸润及功能活化：斑块内CCR7阳性DC含量增加,主要分布于斑块的肩部或斑块核心的边缘区域,并且与T淋巴细胞聚集在一起激活斑块内局部免疫炎症反应。Pio药物干预能抑制内源性AngⅡ所致的斑块内DC浸润,并降低斑块内CCR7阳性DC的含量。
总结：PPAR-γ激动剂Pio能抑制内源性Ang II所致ApoE-/-小鼠动脉粥样硬化发展及斑块不稳定,其可能的机制之一与调节DC介导的免疫炎症反应相关。这些研究结果进一步证实了DC介导的免疫炎症机制在Ang II诱导动脉粥样硬化发展及斑块不稳定中的作用,同时也为临床选择使用PPAR-γ激动剂如噻唑烷二酮类药物以DC为靶点预防和治疗动脉粥样硬化提供科学的理论依据。
Research in vitro:PPAR-y agonist pioglitazone inhibits exogenous angiotensinⅡ-induced activation of dendritic cells via the MAPK and NF-κB pathways
Objective:The renin-angiotensin system exerts a profound regulatory effect on the functional features of dendritic cells (DC), thus suggesting a new target of angiotensinⅡ(Ang II) action in the immune system. This study investigated whether peroxisome proliferator-activated receptor-gamma (PPAR-y) activation in DC with pioglitazone (Pio) regulated AngⅡ-induced activation of DC and exploited the possible molecular mechanisms, especially focused on the signaling pathways of mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB).
Methods:DC derived from human peripheral blood monouclear cells were cultured in vitro and stimulated with exogenous AngⅡin the presence or absence of the PPAR-y agonist Pio. Then, flow cytometry was used for DC phenotypic analysis, enzyme-linked immunosorbent assay for cytokines secretion of DC, mixed lymphocyte reaction for T-cell proliferation stimulated by DC. Furthermore, MAPK phosphorylation state in DC was analyzed by western blot test and NF-κB/DNA binding activity in DC was assayed by electrophoretic mobility shift assay.
Results:Exogenous AngⅡstimulation of human monocyte-derived DC displayed an intermediate state of DC maturation and function characterized of up-regulation of the DC mature marker CD83 and costimulatory molecule CD86 expression but not significant alteration of the costimulatory molecule CD80 and MHC class II molecule HLA-DR, increase secretion of inflammatory cytokines (IL-6 and TNF-a) but not T cell stimulatory cytokines (IL-12), and enhance of allogenic T cell proliferation induced by mature DC but not immature DC. We next pretreated human DC with Pio before Ang II and found that Pio partially inhibited Ang II-induced activation of DC in terms of decrease of CD83 expression but not CD86, reduction of IL-12 and TNF-a secretion but not IL-6, and diminution of T cell activation. In addition, we found that Ang II stimulation of human DC induced the phosphorylation of extracellular regulated kinase (ERK) and p38 MAPK, but not c-Jun N-terminal kinase (JNK). And also AngⅡincreased the DNA binding activity of NF-κB in DC. Finally, when pretreatment of human DC with Pio before Ang II, it was expected that Pio inhibited ERK and p38 MAPK phosphorylation and NF-κB/DNA binding activity in DC induced by AngⅡ.
Conclusions:PPAR-y activation in human DC with Pio inhibits the functional activation of DC induced by Ang II, with which involves the regulation of MAPK and NF-κB signaling pathways. These findings may support the important role of these mediators in the regulation of DC-mediated inflammatory and immunologic processes.
Research in vivo:PPAR-γagonist pioglitazone inhibits endogenous angiotensinⅡ-induced activation of dendritic cells and increase of atherosclerotic plaque vulnerability in apolipoprotein E deficient mice
Objective:Rupture of vulnerable plaques is the main cause of acute cardiovascular events, mechanisms responsible for atherosclerotic plaque destabilization remain elusive. As we had found previously in vitro research that PPAR-γactivation with Pio inhibited the functional activation of DC induced by AngⅡ, we next generated endogenous AngⅡincreased and atherosclerotic ApoE-/- mice to study whether the PPAR-y agonist Pio inhibits the atherosclerotic plaque vulnerability induced by AngⅡin vivo, and exploited the possible mechanisms, especially focused on the inflammatory and immunologic processes mediated by DC.
Methods:Two kidney one clip (2K1C) was operated on ApoE-/- mice to generate endogenous high AngⅡatherosclerotic mouse model, and a sham procedure was applied in control mice. The 2K1C ApoE-/- mice were randomly divided into two groups: one group received the PPAR-y agonist Pio (20 mg/kg/d, orally by gastric gavage), named 2K1C+Pio group; and the other group received equivalent normal saline, named 2K1C group. The sham ApoE-/- mice were also randomly divided into two groups:one group received Pio (20 mg/kg/d, orally by gastric gavage), named sham+Pio group; and the other group received equivalent normal saline, named sham group. After treatment for 12 weeks as the protocol, blood pressure were measured by carotid artery manometry, lipid profile and glucose level in blood were detected by biochemical test, plasma rennin activity (PRA) and concentration of AngⅡwere examined by radioimmunology assay. Aortic arch photos and thoracic and abdominal aorta staining with oil-red O were prepared to estimate the plaque burden. The root of aorta was dissected and sections were performed with hematoxylin and eosin staining and smooth muscle cell a-actin immunohistostaining to evaluate the plaque vulnerability, and CD3 immunohistostaining for T lymphocytes, S-100 and C-C chemokine receptor type 7 (CCR7) immunohistochemistry double staining for DC to detect the infiltrating and functional status of immune cells in atherosclerotic plaques.
Results:The endogenous high Ang II atherosclerotic mouse model was successfully created. As expected, the blood pressure, PRA and AngⅡwere significantly increased in 2K1C ApoE-/- mice. Treatment of Pio exhibited no difference in blood pressure and Ang II concentration, although higher PRA compared with sham ApoE-/- mice. No difference in body weight, heart rate, lipid profile and glucose level was observed among the various groups of mice. Endogenous high AngⅡin 2K1C ApoE-/- mice promoted atherosclerosis progression in terms of increased plaque burden and enlarged plaque area in aortas; and also led to plaque vulnerability with larger lipid core, thinner fibrous cap or even rupture, decreased smooth muscle cells and increased T lymphocytes in plaques. However, Pio treatment significantly prevented the progression of atherosclerosis in 2K1C ApoE-/- mice in terms of reduced plaque burden and decreased plaque area in aortas; and also inhibited the plaque vulnerability by reducing lipid core, thickening fibrous cap, increasing content of smooth muscle cells and decreasing T lymphocytes infiltrating in plaques. Further study revealed that endogenous high Ang II in 2K1C ApoE-/- mice induced infiltrating and activation of DC in atherosclerotic plaque in terms of increased CCR7 positive DC accumulating in the plaque shoulder and in the marginal parts of the plaque core together with T lymphocytes. In addition, Pio treatment of 2K1C ApoE-/- mice obviously inhibited DC infiltratiing and activation in the atherosclerotic plaque induced by endogenous high AngⅡ.
Conclusion:PPAR-γagonist Pio inhibits the atherosclerosis progression and plaque vulnerability induced by endogenous AngⅡin ApoE-/- mouse, with which involves the regulation of the inflammatory and immunologic processes mediated by DC. These findings may support the important role of DC-mediated inflammatory and immunologic mechanism in atherosclerosis progression and plaque vulnerability induced by AngⅡ. That may also provide us more scientific evidence for the potential beneficial effects of PPAR-γagonists such as thiazolidinediones in the prevention or treatment of atherosclerosis.
目的：肾素血管紧张素系统在树突状细胞(dendritic cell, DC)上表达并具有功能活性,提示血管紧张素Ⅱ(angiotensinⅡ, AngⅡ)可能通过调节DC功能在免疫炎症反应过程中发挥重要的作用。本部分体外研究过氧化物酶体增生物激活受体-γ(peroxisome protiferator activated receptor-gamma, PPAR-γ)激动剂吡格列酮(pioglitazone, Pio)对外源性AngⅡI诱导DC功能活化的影响,并进一步探讨其内在的信号转导机制。
方法：体外分离培养人外周血单核细胞来源的DC,直接加入AngⅡ干预,或者经PPAR-γ激动剂Pio预处理后再加入AngⅡ干预。然后采用流式细胞学技术检测DC表达表型分子CD80、CD86、CD83和HLA-DR的功能,酶联免疫吸附试验检测DC分泌细胞因子IL-6、TNF-α和IL-12的功能,混合淋巴细胞反应检测DC刺激T淋巴细胞增殖的功能。进一步通过蛋白印迹试验检测DC内丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)的磷酸化,电泳迁移率转变试验检测DC内核因子-κB(nuclear factor kappa B, NF-κB)的活性。
结果：外源性AngⅡ的刺激能上调人单核细胞来源DC表面的成熟标记分子CD83和共刺激分子CD86,但对共刺激分子CD80和MHC-II类分子HLA-DR的表达无显著影响；能促进DC分泌炎症因子IL-6和TNF-a,但对T淋巴细胞刺激因子IL-12分泌的促进作用不明显；能显著增强成熟DC刺激的T淋巴细胞增殖反应,但对未成熟DC刺激T淋巴细胞增值能力的增加不明显。经PPAR-γ激动剂Pio预处理能明显抑制AngⅡ诱导DC上调CD83分子表达,但对AngⅡ上调CD86分子表达无显著影响；能减少Ang II促进DC分泌IL-12和TNF-a,但对Ang II刺激IL-6分泌影响不大；Pio还能够阻断Ang II协同刺激DC激活T淋巴细胞增殖反应。进一步研究发现,外源性AngⅡ刺激人单核细胞来源DC能促进DC内细胞外信号调节激酶(extracellular signal-related kinase, ERK)和P38 MAPK的磷酸化,但对c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)磷酸化的作用不明显；还能增强DC内NF-κB/DNA结合活性。经PPAR-y激动剂Pio预处理能明显抑制AngⅡ促进DC内ERK和P38 MAPK的磷酸化,而且还能降低AngⅡ增强的DC内NF-κB/DNA结合活性。
总结：PPAR-γ激动剂Pio能抑制外源性AngⅡ诱导DC功能活化,其内在的分子机制至少部分是通过阻断MAPK和NF-κB信号转导通路实现的。这些研究的发现进一步证实了上述多种介质相互作用在调节DC介导的免疫炎症过程中具有十分重要的作用。
体内研究：PPAR-y激动剂吡格列酮抑制内源性血管紧张素Ⅱ致ApoE基因缺陷小鼠动脉粥样硬化斑块不稳定及其免疫炎症机制
目的：动脉粥样硬化易损斑块破裂是引起急性心血管事件的主要原因,但是导致斑块失稳的具体机制至今仍未完全阐明。在前面的体外研究中我们已经发现PPAR-γ激动剂Pio能抑制外源性AngⅡ诱导DC功能活化,本部分实验通过建立内源性高AngⅡ动脉粥样硬化小鼠模型,研究在体情况下PPAR-γ激动剂Pio对内源性Ang II诱导ApoE-/-小鼠动脉粥样硬化斑块不稳定的影响,并进一步探讨DC介导的免疫炎症机制在动脉粥样硬化斑块易损中的作用。
方法：在Apo-/-小鼠的基础上进行两肾一夹(two kidney one clip,2K1C)手术,建立内源性高AngⅡ动脉粥样硬化小鼠模型,另行假手术作为对照。2K1C术后小鼠分成两组,其中一组予PPAR-y激动剂Pio 20 mg/kg/d灌胃,称为2K1C+Pio组,另一组予等量生理盐水灌胃,称为2K1C组；假手术小鼠也分成两组,其中一组予Pio 20 mg/kg/d灌胃,称为sham+Pio组,另一组予等量生理盐水灌胃,称为sham组。各组小鼠严格按照实验计划连续处理12周,然后经有创颈动脉测压法测定动脉血压,常规生化检测血脂、血糖水平,放射免疫法检测血浆肾素活性和Ang II浓度；主动脉弓大体照片和胸腹主动脉油红O染色观测主动脉斑块负荷,主动脉根部组织切片苏木精-伊红染色和平滑肌细胞肌动蛋白免疫组化染色评价斑块易损性,CD3免疫组化染色T淋巴细胞,S-100蛋白和C-C家族趋化因子受体-7(C-C chemokine receptor type 7, CCR7)免疫组化双染色DC检测斑块内免疫炎症细胞的浸润及功能状态。
结果：成功建立内源性高Ang II动脉粥样硬化小鼠模型,2K1C术后ApoE-/-小鼠动脉血压显著增高,血浆肾素活性明显增强,Ang II浓度显著增高；Pio药物干预以后ApoE-/-小鼠动脉血压无明显变化,虽然血浆肾素活性增强,但Ang II浓度未见明显差异；2K1C术后和Pio药物干预对ApoE-/-小鼠体重、心率,血脂、血糖水平均无明显影响。2K1C术后所致的内源性高Ang II能促进ApoE-/-小鼠动脉粥样硬化发展：主动脉弓和胸腹主动脉的斑块负荷增加,斑块面积增大；还能促进斑块易损性：斑块脂质核心增大,纤维帽变薄甚至破坏,斑块内平滑肌细胞含量减少,T淋巴细胞浸润增加。Pio药物治疗能延缓内源性Ang II所致的ApoE-/-小鼠动脉粥样硬化进展：主动脉弓和胸腹主动脉的斑块负荷降低,斑块面积减少；还能抑制斑块的易损性：脂质核心减小,纤维帽增厚并且连续完整,斑块内平滑肌细胞含量增加,T淋巴细胞浸润减少。进一步研究发现,2K1C术后所致的内源性高Ang II能促进ApoE-/-小鼠动脉粥样硬化斑块内DC浸润及功能活化：斑块内CCR7阳性DC含量增加,主要分布于斑块的肩部或斑块核心的边缘区域,并且与T淋巴细胞聚集在一起激活斑块内局部免疫炎症反应。Pio药物干预能抑制内源性AngⅡ所致的斑块内DC浸润,并降低斑块内CCR7阳性DC的含量。
总结：PPAR-γ激动剂Pio能抑制内源性Ang II所致ApoE-/-小鼠动脉粥样硬化发展及斑块不稳定,其可能的机制之一与调节DC介导的免疫炎症反应相关。这些研究结果进一步证实了DC介导的免疫炎症机制在Ang II诱导动脉粥样硬化发展及斑块不稳定中的作用,同时也为临床选择使用PPAR-γ激动剂如噻唑烷二酮类药物以DC为靶点预防和治疗动脉粥样硬化提供科学的理论依据。
Research in vitro:PPAR-y agonist pioglitazone inhibits exogenous angiotensinⅡ-induced activation of dendritic cells via the MAPK and NF-κB pathways
Objective:The renin-angiotensin system exerts a profound regulatory effect on the functional features of dendritic cells (DC), thus suggesting a new target of angiotensinⅡ(Ang II) action in the immune system. This study investigated whether peroxisome proliferator-activated receptor-gamma (PPAR-y) activation in DC with pioglitazone (Pio) regulated AngⅡ-induced activation of DC and exploited the possible molecular mechanisms, especially focused on the signaling pathways of mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB).
Methods:DC derived from human peripheral blood monouclear cells were cultured in vitro and stimulated with exogenous AngⅡin the presence or absence of the PPAR-y agonist Pio. Then, flow cytometry was used for DC phenotypic analysis, enzyme-linked immunosorbent assay for cytokines secretion of DC, mixed lymphocyte reaction for T-cell proliferation stimulated by DC. Furthermore, MAPK phosphorylation state in DC was analyzed by western blot test and NF-κB/DNA binding activity in DC was assayed by electrophoretic mobility shift assay.
Results:Exogenous AngⅡstimulation of human monocyte-derived DC displayed an intermediate state of DC maturation and function characterized of up-regulation of the DC mature marker CD83 and costimulatory molecule CD86 expression but not significant alteration of the costimulatory molecule CD80 and MHC class II molecule HLA-DR, increase secretion of inflammatory cytokines (IL-6 and TNF-a) but not T cell stimulatory cytokines (IL-12), and enhance of allogenic T cell proliferation induced by mature DC but not immature DC. We next pretreated human DC with Pio before Ang II and found that Pio partially inhibited Ang II-induced activation of DC in terms of decrease of CD83 expression but not CD86, reduction of IL-12 and TNF-a secretion but not IL-6, and diminution of T cell activation. In addition, we found that Ang II stimulation of human DC induced the phosphorylation of extracellular regulated kinase (ERK) and p38 MAPK, but not c-Jun N-terminal kinase (JNK). And also AngⅡincreased the DNA binding activity of NF-κB in DC. Finally, when pretreatment of human DC with Pio before Ang II, it was expected that Pio inhibited ERK and p38 MAPK phosphorylation and NF-κB/DNA binding activity in DC induced by AngⅡ.
Conclusions:PPAR-y activation in human DC with Pio inhibits the functional activation of DC induced by Ang II, with which involves the regulation of MAPK and NF-κB signaling pathways. These findings may support the important role of these mediators in the regulation of DC-mediated inflammatory and immunologic processes.
Research in vivo:PPAR-γagonist pioglitazone inhibits endogenous angiotensinⅡ-induced activation of dendritic cells and increase of atherosclerotic plaque vulnerability in apolipoprotein E deficient mice
Objective:Rupture of vulnerable plaques is the main cause of acute cardiovascular events, mechanisms responsible for atherosclerotic plaque destabilization remain elusive. As we had found previously in vitro research that PPAR-γactivation with Pio inhibited the functional activation of DC induced by AngⅡ, we next generated endogenous AngⅡincreased and atherosclerotic ApoE-/- mice to study whether the PPAR-y agonist Pio inhibits the atherosclerotic plaque vulnerability induced by AngⅡin vivo, and exploited the possible mechanisms, especially focused on the inflammatory and immunologic processes mediated by DC.
Methods:Two kidney one clip (2K1C) was operated on ApoE-/- mice to generate endogenous high AngⅡatherosclerotic mouse model, and a sham procedure was applied in control mice. The 2K1C ApoE-/- mice were randomly divided into two groups: one group received the PPAR-y agonist Pio (20 mg/kg/d, orally by gastric gavage), named 2K1C+Pio group; and the other group received equivalent normal saline, named 2K1C group. The sham ApoE-/- mice were also randomly divided into two groups:one group received Pio (20 mg/kg/d, orally by gastric gavage), named sham+Pio group; and the other group received equivalent normal saline, named sham group. After treatment for 12 weeks as the protocol, blood pressure were measured by carotid artery manometry, lipid profile and glucose level in blood were detected by biochemical test, plasma rennin activity (PRA) and concentration of AngⅡwere examined by radioimmunology assay. Aortic arch photos and thoracic and abdominal aorta staining with oil-red O were prepared to estimate the plaque burden. The root of aorta was dissected and sections were performed with hematoxylin and eosin staining and smooth muscle cell a-actin immunohistostaining to evaluate the plaque vulnerability, and CD3 immunohistostaining for T lymphocytes, S-100 and C-C chemokine receptor type 7 (CCR7) immunohistochemistry double staining for DC to detect the infiltrating and functional status of immune cells in atherosclerotic plaques.
Results:The endogenous high Ang II atherosclerotic mouse model was successfully created. As expected, the blood pressure, PRA and AngⅡwere significantly increased in 2K1C ApoE-/- mice. Treatment of Pio exhibited no difference in blood pressure and Ang II concentration, although higher PRA compared with sham ApoE-/- mice. No difference in body weight, heart rate, lipid profile and glucose level was observed among the various groups of mice. Endogenous high AngⅡin 2K1C ApoE-/- mice promoted atherosclerosis progression in terms of increased plaque burden and enlarged plaque area in aortas; and also led to plaque vulnerability with larger lipid core, thinner fibrous cap or even rupture, decreased smooth muscle cells and increased T lymphocytes in plaques. However, Pio treatment significantly prevented the progression of atherosclerosis in 2K1C ApoE-/- mice in terms of reduced plaque burden and decreased plaque area in aortas; and also inhibited the plaque vulnerability by reducing lipid core, thickening fibrous cap, increasing content of smooth muscle cells and decreasing T lymphocytes infiltrating in plaques. Further study revealed that endogenous high Ang II in 2K1C ApoE-/- mice induced infiltrating and activation of DC in atherosclerotic plaque in terms of increased CCR7 positive DC accumulating in the plaque shoulder and in the marginal parts of the plaque core together with T lymphocytes. In addition, Pio treatment of 2K1C ApoE-/- mice obviously inhibited DC infiltratiing and activation in the atherosclerotic plaque induced by endogenous high AngⅡ.
Conclusion:PPAR-γagonist Pio inhibits the atherosclerosis progression and plaque vulnerability induced by endogenous AngⅡin ApoE-/- mouse, with which involves the regulation of the inflammatory and immunologic processes mediated by DC. These findings may support the important role of DC-mediated inflammatory and immunologic mechanism in atherosclerosis progression and plaque vulnerability induced by AngⅡ. That may also provide us more scientific evidence for the potential beneficial effects of PPAR-γagonists such as thiazolidinediones in the prevention or treatment of atherosclerosis.
引文
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