Sukhanov Sergiy, Snarski Patricia, Vaughn Charlotte, Lobelle-Rich Patricia, Kim Catherine, Higashi Yusuke, Shai Shaw-Yung, Delafontaine Patrice
Heart and Vascular Institute, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
Heart and Vascular Institute, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
Atherosclerosis. 2015 Feb;238(2):313-20. doi: 10.1016/j.atherosclerosis.2014.12.024. Epub 2014 Dec 20.
We have shown that insulin-like growth factor I (IGF-1) infusion in Apoe(-/-) mice decreased atherosclerotic plaque size and plaque macrophage and lipid content suggesting that IGF-1 suppressed formation of macrophage-derived foam cells. Since 12/15-lipoxygenase (12/15-LOX) plays an important role in OxLDL and foam cell formation, we hypothesized that IGF-1 downregulates 12/15-LOX, thereby suppressing lipid oxidation and foam cell formation.
We found that IGF-1 decreased 12/15-LOX plaque immunopositivity and serum OxLDL levels in Apoe(-/-) mice. IGF-1 reduced 12/15-LOX protein and mRNA levels in cultured THP-1 macrophages and IGF-1 also decreased expression of STAT6 transcription factor. IGF-1 reduction in macrophage 12/15-LOX was mediated in part via a PI3 kinase- and STAT6-dependent transcriptional mechanism. IGF-1 suppressed THP-1 macrophage ability to oxidize lipids and form foam cells. IGF-1 downregulated 12/15-LOX in human blood-derived primary macrophages and IGF-1 decreased LDL oxidation induced by these cells. IGF-1 reduced LDL oxidation and formation of foam cells by wild type murine peritoneal macrophages, however these effects were completely blocked in 12/15-LOX-null macrophages suggesting that the ability of IGF-1 to reduce LDL oxidation and foam cells formation is dependent on its ability to downregulate 12/15-LOX.
Overall our data demonstrate that IGF-1 reduces lipid oxidation and foam cell formation via downregulation of 12/15-LOX and this mechanism may play a major role in the anti-atherosclerotic effects of IGF-1.
我们已经表明，在载脂蛋白E基因敲除（Apoe(-/-)）小鼠中输注胰岛素样生长因子I（IGF-1）可减小动脉粥样硬化斑块大小，并降低斑块中的巨噬细胞和脂质含量，这表明IGF-1抑制了巨噬细胞源性泡沫细胞的形成。由于12/15-脂氧合酶（12/15-LOX）在氧化型低密度脂蛋白（OxLDL）和泡沫细胞形成中起重要作用，我们推测IGF-1下调12/15-LOX，从而抑制脂质氧化和泡沫细胞形成。
我们发现IGF-1降低了Apoe(-/-)小鼠中12/15-LOX斑块免疫阳性率和血清OxLDL水平。IGF-1降低了培养的THP-1巨噬细胞中12/15-LOX蛋白和mRNA水平，并且IGF-1还降低了信号转导和转录激活因子6（STAT6）转录因子的表达。IGF-1对巨噬细胞中12/15-LOX的降低部分是通过磷脂酰肌醇-3激酶（PI3激酶）和STAT6依赖性转录机制介导的。IGF-1抑制了THP-1巨噬细胞氧化脂质和形成泡沫细胞的能力。IGF-1下调了人血源性原代巨噬细胞中的12/15-LOX，并且IGF-1降低了这些细胞诱导的低密度脂蛋白（LDL）氧化。IGF-1降低了野生型小鼠腹腔巨噬细胞的LDL氧化和泡沫细胞形成，然而在12/15-LOX基因敲除的巨噬细胞中这些作用被完全阻断，这表明IGF-1降低LDL氧化和泡沫细胞形成的能力取决于其下调12/15-LOX的能力。
总体而言，我们的数据表明IGF-1通过下调12/15-LOX来降低脂质氧化和泡沫细胞形成，并且这种机制可能在IGF-1的抗动脉粥样硬化作用中起主要作用。
