Department of Diabetes, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Am J Physiol Heart Circ Physiol. 2010 Mar;298(3):H736-45. doi: 10.1152/ajpheart.00935.2009. Epub 2009 Dec 11.
Diabetes is associated with significantly accelerated rates of atherosclerosis, key features of which include the presence of excessive macrophage-derived foam cells in the subendothelial space. We examined the hypothesis that enhanced monocyte-vascular smooth muscle cell (VSMC) interactions leading to subendothelial monocyte retention and differentiation to macrophages under diabetic conditions may be underlying mechanisms. Human aortic VSMCs (HVSMCs) treated with diabetic stimuli high glucose (HG) or S100B, a ligand of the receptor for advanced glycation end products, exhibited significantly increased binding of THP-1 monocytic cells. Diabetic stimuli increased the expression of the adhesive chemokine fractalkine (FKN) in HVSMCs. Pretreatment of HVSMCs with FKN or monocyte chemoattractant protein-1 (MCP-1) neutralizing antibodies significantly inhibited monocyte-VSMC binding, whereas monocytes treated with FKN showed enhanced binding to VSMC. Mouse aortic VSMCs (MVSMCs) derived from type 2 diabetic db/db mice exhibited significantly increased FKN levels and binding to mouse WEHI78/24 monocytic cells relative to nondiabetic control db/+ cells. The enhanced monocyte binding in db/db cells was abolished by both FKN and MCP-1 antibodies. Endothelium-denuded aortas from db/db mice and streptozotocin-induced diabetic mice also exhibited enhanced FKN expression and monocyte binding, relative to respective controls. Coculture with HVSMCs increased CD36 expression in THP-1 cells, and this was significantly augmented by treatment of HVSMCs with S100B or HG. CD36 mRNA and protein levels were also significantly increased in WEHI78/24 cells after coincubation with db/db MVSMCs relative to control MVSMCs. These results demonstrate that diabetic conditions may accelerate atherosclerosis by inducing key chemokines in the vasculature that promote VSMC-monocyte interactions, subendothelial monocyte retention, and differentiation.
糖尿病与动脉粥样硬化的加速发展密切相关，其主要特征包括在内皮下空间存在过多的巨噬细胞源性泡沫细胞。我们检验了这样一个假说，即在糖尿病条件下，增强单核细胞与血管平滑肌细胞（VSMC）的相互作用，导致内皮下单核细胞的保留和向巨噬细胞的分化，可能是潜在的机制。用高糖（HG）或晚期糖基化终产物受体配体 S100B 处理的人主动脉平滑肌细胞（HVSMCs），与 THP-1 单核细胞的结合显著增加。糖尿病刺激物增加了 HVSMCs 中黏附趋化因子 fractalkine（FKN）的表达。HVSMCs 用 FKN 或单核细胞趋化蛋白-1（MCP-1）中和抗体预处理，显著抑制单核细胞与 VSMC 的结合，而 FKN 处理的单核细胞显示出与 VSMC 结合的增强。源自 2 型糖尿病 db/db 小鼠的鼠主动脉平滑肌细胞（MVSMCs）表现出显著增加的 FKN 水平和与鼠 WEHI78/24 单核细胞的结合，与非糖尿病对照 db/+细胞相比。db/db 细胞中增强的单核细胞结合被 FKN 和 MCP-1 抗体均消除。db/db 小鼠和链脲佐菌素诱导的糖尿病小鼠的去内皮主动脉也表现出增强的 FKN 表达和单核细胞结合，与各自的对照相比。与 HVSMCs 共培养增加了 THP-1 细胞中 CD36 的表达，而 HVSMCs 用 S100B 或 HG 处理后，这种表达显著增强。与对照 MVSMCs 相比，与 db/db MVSMCs 共孵育后，WEHI78/24 细胞中的 CD36 mRNA 和蛋白水平也显著增加。这些结果表明，糖尿病条件可能通过诱导血管中的关键趋化因子来加速动脉粥样硬化，这些趋化因子促进 VSMC-单核细胞相互作用、内皮下单核细胞的保留和分化。
