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.

中文翻译：

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层流剪切应力激活血红素加氧酶-1可改善高糖诱导的内皮细胞和平滑肌细胞功能障碍

高葡萄糖（HG）诱导的内皮细胞（EC）和平滑肌细胞（SMC）功能障碍对于糖尿病相关的动脉粥样硬化至关重要。然而，血红素加氧酶-1 (HO-1)（一种应激反应蛋白）在血流动力学力产生的剪切应力和 HG 诱导的代谢应激中的作用仍不清楚。这项研究检查了 HG 处理的 EC 和邻近 SMC 中生理高剪切应力 (HSS) 下 HO-1 的细胞效应和机制。我们发现人主动脉内皮细胞暴露于 HSS 显着增加了 HO-1 的表达；然而，这种上调似乎与单磷酸腺苷激活蛋白激酶（HO-1 的调节因子）无关。此外，HSS 抑制 HG 诱导的细胞间粘附分子-1、血管细胞粘附分子-1 的表达以及 EC 中活性氧 (ROS) 的产生。在 EC/SMC 共培养中，与静态条件相比，对靠近 SMC 的 EC 进行 HSS 和 HG 显着抑制 SMC 增殖，同时增加生理收缩表型标记物的表达，例如 α-平滑肌肌动蛋白和血清反应因子。此外，HSS 和 HG 降低了 SMC 中波形蛋白（一种致动脉粥样硬化的合成表型标记物）的表达。用 HO-1 特异性小干扰 (si)RNA 转染 EC，可逆转 HSS 对 EC 中 HG 诱导的炎症和 ROS 产生的抑制。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抑制作用被逆转。我们的研究结果提供了对 HG 诱导的代谢应激期间 EC-SMC 相互作用的潜在机制的见解。促进血管壁 HSS 的策略，例如持续运动，或开发 HO-1 类似物和 HSS 效应模拟物，可以为预防和治疗糖尿病相关的动脉粥样硬化血管并发症提供有效的方法。