血管内皮细胞IRS1的过度表达以及胰岛素水平提高可减少粥样硬化
血管内皮细胞上胰岛素受体和活性的减少导致了粥样硬化风险的增加。尽管如此，没有研究表面内皮上胰岛素信号直接增强可以减少正常或者胰岛素耐受个体粥样硬化。
为了通过PI3K/Akt/eNOS通路增强胰岛素的抗粥样硬化活性，我们利用在ApoE-/-背景(IRS1/ApoE-/- mice)由内皮特异性VE-钙粘着蛋白启动子过度表达RS1 on ApoE-/-的转基因小鼠。免疫印迹和免疫细胞化学分析来确证IRS1是在内皮细胞核主动脉上是特异性的过度表达2.7倍，在股动脉的胰岛素信号显示其p-Akt/eNOS在IRS1/ApoE-/- vs ApoE-/-小鼠上增强了2.5倍。
进行24周后的高脂肪饮食，再进行en face染色进行动脉硬化斑块良好显示斑块减少了46% ± 11% (p<0.05)。斑块大小显示减少了40% ± 20% (p<0.05)，细胞外基质减少了37% ± 14% (p<0.05)，平滑肌细胞减少了27% ± 7% (p<0.05)及巨噬细胞减少了33% ± 11% (p<0.05)。VCAM-1和ICAM-1 mRNA表达水平同样分别减少了53% ± 17%和47% ± 13%(p<0.05)，同时p-eNOS的水平在IRS1/ApoE-/- vs. ApoE-/-小鼠上增加了3.6倍。
功能化研究测定的白细胞-内皮细胞绑定由IRS1/ApoE-/-vs ApoE-/-小鼠氧化LDL刺激下降了43% ± 20%。这一研究第一次证明了增强的胰岛素IRS1/Akt通路活性可以降低HFD-诱导的粥样硬化。这些方向同时支持了一种令人兴奋的可能性，既针对内皮细胞上胰岛素IRS1 /Akt通路激活将降低糖尿病和胰岛素抵抗状态个体粥样硬化风险。
Loss of insulin receptors or actions on the endothelium contributes to the increased risk of atherosclerosis. However，no study has documented that enhancement of insulin signaling directly in theendothelium can decrease atherosclerosis in normal or insulin resistant states.
To enhance insulin's anti-atherogenic action via PI3K/Akt/eNOS pathway we generated transgenic mice overexpressing IRS1 on ApoE-/- background (IRS1/ApoE-/- mice) driven by endothelial specific VE-cadherin promoter. Immunoblot and immunocytochemistry assay confirmed that IRS1 is specifically overexpressed in endothelial cells and aorta by 2.7-fold. Insulin signaling in the femoral artery showed an enhancement on the activation of p-Akt/eNOS by 2.5-fold in IRS1/ApoE-/- vs ApoE-/-mice. Quantitation of the atherosclerotic plaque by en face staining after 24 weeks of high fat diet (HFD 42%) showed a reduction of plaque by 46% ± 11% (p<0.05). Complexity of the plaque showed a reduction of plaque size by 40% ± 20% (p<0.05) extracellular matrix by 37% ± 14% (p<0.05) smooth muscle cell numbers by 27% ± 7% (p<0.05) and macrophage content by 33% ± 11% (p<0.05). Expression of VCAM-1 and ICAM-1 mRNA levels were also decreased by 53% ± 17% and 47% ± 13% respectively (p<0.05) whereas the levels of p-eNOS were increased by 3.6-fold in IRS1/ApoE-/- vs. ApoE-/- mice.
Functional studies measured by leukocyte-endothelial cell binding when stimulated by oxidized LDL exhibited a reduction of 43% ± 20% in IRS1/ApoE-/-vs ApoE-/- mice. This study provided the first demonstration that enhancing insulin activities via IRS1/Akt pathway can decrease HFD-induced atherosclerosis. These findings also supported the exciting possibility that targeting insulin to activate IRS1/Akt pathway on the endothelium will reduce the risk of atherosclerosis in diabetes and insulin resistant states.
ADA是美国糖尿病学会 (Americn Diabetos Association)的缩写，美国糖尿病协会县美国重要的非赢利性卫生姐织，旨在提供有关糖尿病的研究进展和信息，促进糖尿病的科研、教育、诊疗等，关注一切与糖尿病有关的事务。