Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania.
Department of Kinesiology, The University of Texas at Arlington, Arlington, Texas.
Am J Physiol Heart Circ Physiol. 2022 May 1;322(5):H880-H889. doi: 10.1152/ajpheart.00643.2021. Epub 2022 Apr 1.
Reactive oxygen species (ROS)-mediated reductions in nitric oxide (NO)-dependent dilation are evident in adults with major depressive disorder (MDD); however, the upstream mechanisms remain unclear. Here, we hypothesized that nuclear factor-κB (NF-κB) activation-induced ROS production contributes to microvascular endothelial dysfunction in MDD. Thirteen treatment-naive adults with MDD (6 women; 19-23 yr) and 10 healthy nondepressed adults (HAs; 5 women; 20-25 yr) were tested before and after (open-label design) systemic NF-κB knockdown (nonacetylated salicylate; 3,000-4,500 mg/day × 4 days). Red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh), alone and in combination with NO synthase inhibition [-nitro-l-arginine methyl ester (l-NAME)] or ROS scavenging (apocynin). Serum salicylate concentrations following treatment were not different between groups (22.8 ± 7.4 HAs vs. 20.8 ± 4.3 mg/dL MDD; = 0.46). When compared with HAs, the NO-dependent component of ACh-induced dilation was blunted in adults with MDD before ( = 0.023), but not after ( = 0.27), salsalate treatment. In adults with MDD, the magnitude of improvement in endothelium-dependent dilation following salsalate treatment was inversely related to the degree of functional impairment at baseline ( = 0.43; = 0.025). Localized ROS scavenging improved NO-dependent dilation before ( < 0.01), but not after ( > 0.05), salsalate treatment. Salsalate did not alter systemic concentrations of pro- or anti-inflammatory cytokines (all > 0.05). These data suggest that NF-κB activation, via increased vascular ROS production, contributes to blunted NO-dependent dilation in young adults with MDD but otherwise free of clinical disease. These data provide the first direct evidence for a mechanistic role of vascular inflammation-associated endothelial dysfunction in human depression. Our data indicate that short-term treatment with therapeutic doses of the nuclear factor-κB (NF-κB) inhibitor salsalate improved nitric oxide (NO)-mediated endothelium-dependent dilation in adults with major depressive disorder (MDD). In adults with MDD, acute localized scavenging of reactive oxygen species (ROS) with apocynin improved NO-dependent dilation before, but not after, salsalate administration. These data suggest that activation of NF-κB, in part via stimulation of vascular ROS production, contributes to blunted NO-mediated endothelium-dependent dilation in young adults with MDD.
活性氧（ROS）介导的一氧化氮（NO）依赖性扩张减少在患有重度抑郁症（MDD）的成年人中很明显；然而，上游机制尚不清楚。在这里，我们假设核因子-κB（NF-κB）激活诱导的 ROS 产生导致 MDD 中的微血管内皮功能障碍。13 名未经治疗的 MDD 成年患者（6 名女性；19-23 岁）和 10 名健康非抑郁成年患者（HA；5 名女性；20-25 岁）在（开放性设计）全身 NF-κB 敲低（非乙酰水杨酸；3000-4500mg/天×4 天）前后进行了测试。在单独和与一氧化氮合酶抑制（-硝基-L-精氨酸甲酯（L-NAME））或 ROS 清除（阿朴肉桂酸）联合进行内皮依赖性激动剂乙酰胆碱（ACh）的分级皮内微透析灌注期间，通过激光多普勒血流测量红细胞通量。治疗后两组之间的血清水杨酸盐浓度无差异（22.8±7.4 HA 与 20.8±4.3mg/dL MDD；=0.46）。与 HA 相比，MDD 成人在接受 salsalate 治疗前（=0.023），但在治疗后（=0.27），ACh 诱导的扩张的 NO 依赖性成分减弱。在 MDD 成人中，salsalate 治疗后内皮依赖性扩张改善的程度与基线时功能障碍的程度呈负相关（=0.43；=0.025）。局部 ROS 清除可改善接受 salsalate 治疗前的 NO 依赖性扩张（<0.01），但不能改善治疗后的扩张（>0.05）。Salsalate 未改变全身促炎或抗炎细胞因子的浓度（均>0.05）。这些数据表明，NF-κB 通过增加血管 ROS 产生而激活，导致年轻 MDD 患者的 NO 依赖性扩张减弱，但没有其他临床疾病。这些数据提供了血管炎症相关内皮功能障碍在人类抑郁症中具有机制作用的第一个直接证据。我们的数据表明，用治疗剂量的核因子-κB（NF-κB）抑制剂水杨酸钠短期治疗可改善重度抑郁症（MDD）成年患者的一氧化氮（NO）介导的内皮依赖性扩张。在 MDD 成人中，用阿朴肉桂酸急性局部清除活性氧（ROS）可改善 salsalate 给药前的 NO 依赖性扩张，但不能改善给药后的扩张。这些数据表明，NF-κB 的激活部分通过刺激血管 ROS 的产生，导致年轻 MDD 患者的 NO 介导的内皮依赖性扩张减弱。
