Pitavastatin downregulates expression of the macrophage type B scavenger receptor, CD36
Pitavastatin downregulates expression of the macrophage type B scavenger receptor, CD36
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DOI：
10.1161/01.cir.0000112576.40815.13
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发表时间：
2004-02-17
期刊：
影响因子：
37.8
通讯作者：
Nicholson, AC
中科院分区：
文献类型：
--
作者：
Han, JH;Zhou, XY;Nicholson, AC
背景-匹伐他汀（NK-104）是一种新型的3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，HMG-CoA还原酶是胆固醇生物合成的限速酶。在临床试验中，匹伐他汀已被证明可显著降低血清LDL胆固醇和甘油三酯水平，并增加HDL胆固醇。清道夫受体介导的氧化低密度脂蛋白（OxLDL）衍生的胆固醇酯的积累被认为是动脉粥样硬化泡沫细胞形成发展的关键步骤。我们研究了匹伐他汀对CD 36（一种B类清道夫受体）表达的影响，由鼠macrophage.Methods和Results -治疗J774细胞和小鼠腹腔巨噬细胞与匹伐他汀降低CD 36 mRNA的表达，在剂量依赖性的方式。在人THP-1细胞和人单核细胞源性巨噬细胞中，CD 36 mRNA的降低与CD 36细胞表面蛋白表达的降低相关。匹伐他汀还减少了过氧化物酶体增殖物激活受体γ（PPARgamma）配体和/或OxLDL诱导的CD 36 mRNA、细胞表面蛋白和OxLDL结合/摄取的增加。匹伐他汀不改变CD 36 mRNA的半衰期，这表明匹伐他汀通过减少CD 36转录下调CD 36表达。此外，匹伐他汀显著降低PPARgamma mRNA和蛋白表达。最后，匹伐他汀增加p44/42丝裂原活化蛋白激酶活性和PPARgamma磷酸化，并增加磷酸化PPARgamma的比例nonphosphorylatedPPARgamma.Conclusions -目前的数据表明，匹伐他汀通过PPARgamma依赖性抑制CD 36的表达，并表明匹伐他汀可以调节CD 36介导的动脉粥样硬化泡沫细胞的形成，防止巨噬细胞摄取OxLDL。
Background - Pitavastatin (NK-104) is a novel inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol biosynthesis. In clinical trials, pitavastatin has been shown to significantly decrease serum LDL cholesterol and triglyceride levels and increase HDL cholesterol. Scavenger receptor - mediated accumulation of oxidized LDL ( OxLDL) - derived cholesteryl ester is considered to be a critical step in the development of atherosclerotic foam cell formation. We studied the effect of pitavastatin on CD36 ( a class B scavenger receptor) expression by murine macrophages.Methods and Results - Treatment of J774 cells and murine peritoneal macrophages with pitavastatin decreased CD36 mRNA expression in a dose-dependent manner. Decreased CD36 mRNA was associated with decreased CD36 cell surface protein expression in human THP-1 cells and human monocyte-derived macrophages. Pitavastatin also reduced the increase in CD36 mRNA, cell surface protein, and binding/uptake of OxLDL induced by peroxisome proliferator activated receptor-gamma (PPARgamma) ligands and/or OxLDL. Pitavastatin did not alter the half-life of CD36 mRNA, which suggests pitavastatin downregulates CD36 expression by reducing CD36 transcription. In addition, pitavastatin significantly decreased PPARgamma mRNA and protein expression. Finally, pitavastatin increased p44/42 mitogen-activated protein kinase activity and PPARgamma phosphorylation and increased the ratio of phosphorylated PPARgamma to nonphosphorylated PPARgamma.Conclusions - The present data demonstrate that pitavastatin prevents OxLDL uptake by macrophages through PPARgamma-dependent inhibition of CD36 expression and suggest that pitavastatin could modulate CD36-mediated atherosclerotic foam cell formation.