Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Atherosclerosis. 2019 Jul;286:30-39. doi: 10.1016/j.atherosclerosis.2019.04.229. Epub 2019 May 3.
Local macrophage proliferation is linked to enhanced atherosclerosis progression. Our previous study found that troglitazone, a thiazolidinedione (TZD), suppressed oxidized low-density lipoprotein (Ox-LDL)-induced macrophage proliferation. However, its effects and mechanisms are unclear. Therefore, we investigated the effects of pioglitazone, another TZD, on macrophage proliferation.
Normal chow (NC)- or high-fat diet (HFD)-fed apolipoprotein E-deficient (Apoe) mice were treated orally with pioglitazone (10 mg/kg/day) or vehicle (water) as a control. Mouse peritoneal macrophages were used in in vitro assays.
Atherosclerosis progression was suppressed in aortic sinuses of pioglitazone-treated Apoe mice, which showed fewer proliferating macrophages in plaques. Pioglitazone suppressed Ox-LDL-induced macrophage proliferation in a dose-dependent manner. However, treatment with peroxisome proliferator-activated receptor-γ (PPARγ) siRNA ameliorated pioglitazone-induced suppression of macrophage proliferation. Low concentrations (less than 100 μmol/L) of pioglitazone, which can suppress macrophage proliferation, activated PPARγ in macrophages, but did not induce macrophage apoptosis. Pioglitazone treatment did not induce TUNEL-positive cells in atherosclerotic plaques of aortic sinuses in Apoe mice.
Pioglitazone suppressed macrophage proliferation through PPARγ without inducing macrophage apoptosis. These findings imply that pioglitazone could prevent macrovascular complications in diabetic individuals.
局部巨噬细胞增殖与动脉粥样硬化进展增强有关。我们之前的研究发现，噻唑烷二酮（TZD）曲格列酮可抑制氧化型低密度脂蛋白（Ox-LDL）诱导的巨噬细胞增殖。然而，其作用和机制尚不清楚。因此，我们研究了另一种 TZD——吡格列酮对巨噬细胞增殖的影响。
用正常饮食（NC）或高脂肪饮食（HFD）喂养载脂蛋白 E 缺陷（Apoe）小鼠，经口给予吡格列酮（10mg/kg/天）或作为对照的载体（水）。在体外实验中使用小鼠腹腔巨噬细胞。
吡格列酮治疗的 Apoe 小鼠主动脉窦中的动脉粥样硬化进展受到抑制，斑块中增殖的巨噬细胞较少。吡格列酮呈剂量依赖性抑制 Ox-LDL 诱导的巨噬细胞增殖。然而，用过氧化物酶体增殖物激活受体-γ（PPARγ）siRNA 处理可改善吡格列酮诱导的巨噬细胞增殖抑制。低浓度（低于 100μmol/L）的吡格列酮可抑制巨噬细胞增殖，但不诱导巨噬细胞凋亡，从而激活巨噬细胞中的 PPARγ。吡格列酮治疗不会诱导 Apoe 小鼠主动脉窦粥样硬化斑块中的 TUNEL 阳性细胞。
吡格列酮通过 PPARγ抑制巨噬细胞增殖，而不诱导巨噬细胞凋亡。这些发现表明，吡格列酮可能预防糖尿病个体的大血管并发症。
