Cohen Katie E, Katunaric Boran, Schulz Mary E, SenthilKumar Gopika, Young Micaela S, Mace James E, Freed Julie K
Department of Medicine-Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI, United States.
Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States.
Front Pharmacol. 2022 Apr 4;13:875900. doi: 10.3389/fphar.2022.875900. eCollection 2022.
Chronic administration of exogenous adiponectin restores nitric oxide (NO) as the mediator of flow-induced dilation (FID) in arterioles collected from patients with coronary artery disease (CAD). Here we hypothesize that this effect as well as NO signaling during flow during health relies on activation of Adiponectin Receptor 1 (AdipoR1). We further posit that osmotin, a plant-derived protein and AdipoR1 activator, is capable of eliciting similar effects as adiponectin. Human arterioles (80-200 μm) collected from discarded surgical adipose specimens were cannulated, pressurized, and pre-constricted with endothelin-1 (ET-1). Changes in vessel internal diameters were measured during flow using videomicroscopy. Immunofluorescence was utilized to compare expression of AdipoR1 during both health and disease. Administration of exogenous adiponectin failed to restore NO-mediated FID in CAD arterioles treated with siRNA against AdipoR1 (siAdipoR1), compared to vessels treated with negative control siRNA. Osmotin treatment of arterioles from patients with CAD resulted in a partial restoration of NO as the mediator of FID, which was inhibited in arterioles with decreased expression of AdipoR1. Together these data highlight the critical role of AdipoR1 in adiponectin-induced NO signaling during shear. Further, osmotin may serve as a potential therapy to prevent microvascular endothelial dysfunction as well as restore endothelial homeostasis in patients with cardiovascular disease.
长期给予外源性脂联素可恢复一氧化氮（NO）作为冠状动脉疾病（CAD）患者小动脉中血流介导的血管舒张（FID）的介质的功能。在此，我们假设这种效应以及健康状态下血流期间的NO信号传导依赖于脂联素受体1（AdipoR1）的激活。我们进一步推测，渗透素，一种植物来源的蛋白质和AdipoR1激活剂，能够引发与脂联素类似的效应。从废弃手术脂肪标本中收集的人小动脉（80 - 200μm）进行插管、加压并用内皮素-1（ET-1）预收缩。使用视频显微镜在血流过程中测量血管内径的变化。利用免疫荧光比较健康和疾病状态下AdipoR1的表达。与用阴性对照小干扰RNA（siRNA）处理的血管相比，给予外源性脂联素未能恢复用针对AdipoR1的siRNA（siAdipoR1）处理的CAD小动脉中NO介导的FID。用渗透素处理CAD患者的小动脉导致部分恢复NO作为FID的介质的功能，这在AdipoR1表达降低的小动脉中受到抑制。这些数据共同突出了AdipoR1在剪切力作用下脂联素诱导的NO信号传导中的关键作用。此外，渗透素可能作为一种潜在的治疗方法，用于预防微血管内皮功能障碍以及恢复心血管疾病患者的内皮稳态。
