Department of Cardiology and Angiology, University of Erlangen-Nuremberg, Erlangen, Germany. Iwona
Clin Hemorheol Microcirc. 2011;48(1):65-73. doi: 10.3233/CH-2011-1394.
Atherosclerotic plaques develop at arterial regions subjected to non-uniform shear stress, and are initiated by increased leukocyte-endothelial interactions. Here we applied the in vitro model of arterial bifurcations to investigate whether telmisartan, an anti-inflammatory angiotensin II receptor blocker with PPAR-gamma activating ability, prevents monocyte recruitment by endothelium.
Human umbilical vein endothelial cells (ECs) were exposed to 18 h non-uniform shear stress in bifurcating flow-through slides, followed by 2 h stimulation with 2.5 ng/mL TNF-alpha. During flow, cells were treated with telmisartan. To study cell adhesion, ECs were perfused with medium containing THP-1 monocytic cells. Adherent THP-1 monocytes were quantified by light microscopy. Endothelial protein expression was determined by immunofluorescence.
Non-uniform shear stress in combination with TNF-alpha dramatically induced monocytic cell recruitment by endothelial cells. In cells treated with telmisartan (0.5-2.5 μmol/L) during exposure to non-uniform shear stress, dose-dependent inhibition of monocytic cell adhesion was observed, with about 45% reduction at 1 μmol/L. This effect was mediated by a significant reduction of endothelial VCAM-1 expression. On the contrary, the induction of E-selectin by TNF-alpha in ECs exposed to non-uniform shear stress was not affected by telmisartan. The inhibitory effect of telmisartan on monocytic cell recruitment and VCAM-1 induction was prevented in the presence of the PPAR-gamma antagonist GW9662.
Treatment with telmisartan decreases the TNF-α-induced recruitment of monocytic cells and endothelial expression of VCAM-1 in regions of non-uniform shear stress in vitro. This mechanism can contribute to the beneficial pleiotropic effects of telmisartan in atherosclerosis-prone arterial regions.
动脉粥样硬化斑块在受非均匀切应力作用的动脉区域发展，并由白细胞-内皮细胞相互作用增加引发。在这里，我们应用动脉分叉的体外模型来研究替米沙坦是否可以预防单核细胞通过内皮细胞募集，替米沙坦是一种具有 PPAR-γ激活能力的抗炎血管紧张素 II 受体阻滞剂。
将人脐静脉内皮细胞（ECs）暴露于分叉流动中的非均匀切应力下 18 小时，然后用 2.5ng/mL TNF-α刺激 2 小时。在流动过程中，用替米沙坦处理细胞。为了研究细胞黏附，将含有 THP-1 单核细胞的培养基灌注到 EC 中。通过相差显微镜定量测定黏附的 THP-1 单核细胞。通过免疫荧光法测定内皮蛋白表达。
非均匀切应力与 TNF-α联合作用可显著诱导单核细胞通过内皮细胞募集。在暴露于非均匀切应力时用替米沙坦（0.5-2.5μmol/L）处理的细胞中，观察到单核细胞黏附的剂量依赖性抑制，在 1μmol/L 时约减少 45%。这种作用是通过内皮细胞 VCAM-1 表达的显著减少介导的。相反，TNF-α诱导的 ECs 中 E-选择素的表达在非均匀切应力下不受替米沙坦的影响。在存在 PPAR-γ拮抗剂 GW9662 的情况下，替米沙坦对单核细胞募集和 VCAM-1 诱导的抑制作用被阻止。
替米沙坦治疗可降低 TNF-α诱导的单核细胞募集和非均匀切应力下 VCAM-1 在体外表达。这种机制可能有助于替米沙坦在动脉粥样硬化易患动脉区域的有益多效作用。
