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

Authors

Kyoungmin Park PhD

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.

编辑： 霄雁    来源：丁香园