Abstract：
High glucose (HG)-induced endothelial cell (EC) and smooth muscle cell (SMC) dysfunction is critical in diabetes-associated atherosclerosis. However, the roles of heme oxygenase-1 (HO-1), a stress-response protein, in hemodynamic force-generated shear stress and HG-induced metabolic stress remain unclear. This investigation examined the cellular effects and mechanisms of HO-1 under physiologically high shear stress (HSS) in HG-treated ECs and adjacent SMCs. We found that exposure of human aortic ECs to HSS significantly increased HO-1 expression; however, this upregulation appeared to be independent of adenosine monophosphate-activated protein kinase, a regulator of HO-1. Furthermore, HSS inhibited the expression of HG-induced intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and reactive oxygen species (ROS) production in ECs. In an EC/SMC co-culture, compared with static conditions, subjecting ECs close to SMCs to HSS and HG significantly suppressed SMC proliferation while increasing the expression of physiological contractile phenotype markers, such as α-smooth muscle actin and serum response factor. Moreover, HSS and HG decreased the expression of vimentin, an atherogenic synthetic phenotypic marker, in SMCs. Transfecting ECs with HO-1-specific small interfering (si)RNA reversed HSS inhibition on HG-induced inflammation and ROS production in ECs. Similarly, reversed HSS inhibition on HG-induced proliferation and synthetic phenotype formation were observed in co-cultured SMCs. Our findings provide insights into the mechanisms underlying EC-SMC interplay during HG-induced metabolic stress. Strategies to promote HSS in the vessel wall, such as continuous exercise, or the development of HO-1 analogs and mimics of the HSS effect, could provide an effective approach for preventing and treating diabetes-related atherosclerotic vascular complications.
摘要：
高糖（HG）诱导的内皮细胞（EC）和平滑肌细胞（SMC）功能障碍在糖尿病相关的动脉粥样硬化中至关重要。然而,血红素加氧酶-1(HO-1)的作用，一种应激反应蛋白，在血流动力学力产生的剪切应力和HG诱导的代谢应激中，尚不清楚。这项研究研究了HO-1在HG处理的EC和相邻SMC中在生理高切应力（HSS）下的细胞作用和机制。我们发现，人主动脉内皮细胞暴露于HSS显著增加HO-1表达；然而，这种上调似乎独立于一磷酸腺苷活化的蛋白激酶，HO-1的调节器。此外，HSS抑制了ECs中HG诱导的细胞间粘附分子1，血管细胞粘附分子1和活性氧（ROS）产生的表达。在EC/SMC共培养中，与静态条件相比，使接近SMC的ECs经受HSS和HG显着抑制SMC增殖，同时增加生理收缩表型标志物的表达，如α-平滑肌肌动蛋白和血清反应因子。此外，HSS和HG降低波形蛋白的表达，一种动脉粥样硬化的合成表型标记，在SMC中。用HO-1特异性小干扰（si）RNA转染ECs可逆转HSS对ECs中HG诱导的炎症和ROS产生的抑制作用。同样，在共培养的SMC中观察到HSS对HG诱导的增殖和合成表型形成的反向抑制。我们的发现为HG诱导的代谢应激过程中EC-SMC相互作用的潜在机制提供了见解。在容器壁上推广HSS的策略，比如连续锻炼，或HO-1类似物的发展和HSS效应的模拟，可为糖尿病相关动脉粥样硬化血管并发症的防治提供有效的途径。
