Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma(PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro.
Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma(PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro.
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发表时间：
1998
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通讯作者：
N. Marx;G. Sukhova;C. Murphy;P. Libby;J. Plutzky
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作者：
N. Marx;G. Sukhova;C. Murphy;P. Libby;J. Plutzky
单核巨噬细胞在动脉粥样硬化及其后遗症斑块破裂中起重要作用，部分是通过其分泌基质金属蛋白酶（MMP-9）。过氧化物酶体增殖物激活受体γ（PPARgamma）是核受体超家族中的一种转录因子，调节基因表达以响应各种激活剂，包括15-脱氧-δ 12，14-前列腺素J2和抗糖尿病药物曲格列酮。PPARgamma在人类动脉粥样硬化中的作用尚未研究。我们在这里报告，单核细胞/巨噬细胞在人类动脉粥样硬化病变（n = 12）表达免疫抑制剂PPARgamma。正常动脉标本（n = 6）显示最低免疫反应性PPARgamma。人单核细胞和单核细胞衍生的巨噬细胞在5%的人血清中培养6天，通过逆转录-聚合酶链反应和蛋白质印迹分别表达PPARgamma mRNA和蛋白质。此外，U937细胞中的PPARgamma mRNA表达在佛波醇12-肉豆蔻酸酯13乙酸酯诱导的分化过程中增加。在人单核细胞衍生的巨噬细胞中，用曲格列酮或15-脱氧-δ 12，14-前列腺素J2刺激PPARgamma以浓度依赖性方式抑制MMP-9的明胶分解活性，如酶谱法所示。这种抑制与通过蛋白质印迹法测定的MMP-9分泌减少相关。因此，PPARgamma存在于人动脉粥样硬化病变的巨噬细胞中，并可调节MMP-9的表达和活性，MMP-9是一种与斑块破裂有关的酶。PPARgamma可能是与人类动脉粥样硬化疾病相关的单核细胞/巨噬细胞功能的重要调节剂。
Mononuclear phagocytes play an important role in atherosclerosis and its sequela plaque rupture in part by their secretion of matrix metalloproteinases (MMPs), including MMP-9. Peroxisomal proliferator-activated receptor gamma (PPARgamma), a transcription factor in the nuclear receptor superfamily, regulates gene expression in response to various activators, including 15-deoxy-delta12,14-prostaglandin J2 and the antidiabetic agent troglitazone. The role of PPARgamma in human atherosclerosis is unexplored. We report here that monocytes/macrophages in human atherosclerotic lesions (n = 12) express immunostainable PPARgamma. Normal artery specimens (n = 6) reveal minimal immunoreactive PPARgamma. Human monocytes and monocyte-derived macrophages cultured for 6 days in 5% human serum expressed PPARgamma mRNA and protein by reverse transcription-polymerase chain reaction and Western blotting, respectively. In addition, PPARgamma mRNA expression in U937 cells increased during phorbol 12-myristate 13 acetate-induced differentiation. Stimulation of PPARgamma with troglitazone or 15-deoxy-delta12,14-prostaglandin J2 in human monocyte-derived macrophages inhibited MMP-9 gelatinolytic activity in a concentration-dependent fashion as revealed by zymography. This inhibition correlates with decreased MMP-9 secretion as determined by Western blotting. Thus, PPARgamma is present in macrophages in human atherosclerotic lesions and may regulate expression and activity of MMP-9, an enzyme implicated in plaque rupture. PPARgamma is likely to be an important regulator of monocyte/macrophage function with relevance for human atherosclerotic disease.