Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
Department of Neurology of Heze Municipal Hospital, Heze, 274000, China.
Hypertens Res. 2024 Aug;47(8):2157-2171. doi: 10.1038/s41440-024-01701-y. Epub 2024 May 21.
Obesity-related hypertension (OH) is accompanied by obvious endothelial dysfunction, which contributes to increased peripheral vascular resistance and hypertension. Adrenomedullin (ADM), a multifunctional active peptide, is elevated in obese humans. The OH rats induced by high fat diet (HFD) for 28 weeks and the human umbilical vein endothelial cells (HUVECs)-treated by palmitic acid (PA) were used to investigate the effects of ADM on endothelial dysfunction and the underlying mechanisms. Vascular reactivity was assessed using mesenteric arteriole rings, and the protein expression levels were examined by Western blot analysis. Compared with the control rats, OH rats exhibited hypertension and endothelial dysfunction, along with reduced eNOS protein expression and Akt activation, and increased protein expression of proinflammatory cytokines and ROS levels. Four-week ADM administration improved hypertension and endothelial function, increased eNOS protein expression and Akt activation, and attenuated endothelial inflammation and oxidative stress in OH rats. In vitro experiment, the antagonism of ADM receptors with ADM22-52 and the suppression of Akt signaling with A6730 significantly blocked ADM-caused increase of NO content and activation of eNOS and Akt, and inhibited the anti-inflammatory and anti-oxidant effect of ADM in PA-stimulated HUVECs. These data indicate that endothelial dysfunction in OH rats is partially attributable to the decreased NO level, and the increased inflammation and oxidative stress. ADM improves endothelial function and exerts hypotensive effect depending on the increase of NO, and its anti-inflammatory and anti-oxidant effect via receptor-Akt pathway.
肥胖相关性高血压（OH）伴有明显的内皮功能障碍，这导致外周血管阻力增加和高血压。肾上腺髓质素（ADM）是一种多功能活性肽，在肥胖人群中升高。用高脂肪饮食（HFD）诱导 28 周的 OH 大鼠和用人脐静脉内皮细胞（HUVEC）处理棕榈酸（PA）来研究 ADM 对内皮功能障碍的影响及其潜在机制。使用肠系膜小动脉环评估血管反应性，并通过 Western blot 分析检查蛋白质表达水平。与对照组大鼠相比，OH 大鼠表现出高血压和内皮功能障碍，同时 eNOS 蛋白表达和 Akt 激活减少，促炎细胞因子和 ROS 水平的蛋白表达增加。四周 ADM 给药改善了 OH 大鼠的高血压和内皮功能，增加了 eNOS 蛋白表达和 Akt 激活，并减轻了 OH 大鼠的内皮炎症和氧化应激。在体外实验中，ADM 受体拮抗剂 ADM22-52 和 Akt 信号通路抑制剂 A6730 显著阻断了 ADM 引起的 NO 含量增加和 eNOS 和 Akt 的激活，并抑制了 PA 刺激的 HUVECs 中 ADM 的抗炎和抗氧化作用。这些数据表明，OH 大鼠的内皮功能障碍部分归因于 NO 水平降低，以及炎症和氧化应激增加。ADM 通过增加 NO 来改善内皮功能并发挥降压作用，通过受体-Akt 通路发挥抗炎和抗氧化作用。
