Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Fourth Military Medical University, Xi'an, China; Teaching Experiment Center, Fourth Military Medical University, Xi'an, China.
Department of Aerospace Medicine, Fourth Military Medical University, Xi'an, China; State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.
Biochem Pharmacol. 2021 Apr;186:114489. doi: 10.1016/j.bcp.2021.114489. Epub 2021 Feb 27.
Hypertension in obesity has become a major threat for public health. Omentin-1, a novel adipokine, is down-regulated in obesity. Tetrahydroxystilbene glycoside (TSG) is the main ingredient extracted from Polygonum multiflorum Thunb (PMT), a traditional Chinese medicinal herb safely used for protecting cardiovascular systems over bimillennium. This study aims to examine (i) the impact of omentin-1 downregulation on obesity-related hypertension in murine models and the underlying mechanisms; (ii) whether tetrahydroxystilbene glycoside (TSG) improved endothelial dysfunction and obesity-associated hypertension via the increase of omentin-1.
(TSG-treated) male Zucker diabetic fatty (ZDF) rats and omentin-1 knockout (OMT) mice were used. In vitro, human umbilical vein endothelial cells (HUVECs) and mature adipocytes differentiated from human visceral preadipocyte (HPA-v) were maintained in a co-culture system.
TSG was the main active component of PMT reducing systolic blood pressure and improving endothelial vasodilation. Fortnight-TSG treatment (100 mg/kg/day) increased serum omentin-1 level, also activated Akt/eNOS signaling and enhanced NO bioactivity; decreased expression of NOX2 and p22, suppressed production of superoxide and peroxynitrite anion. OMT mice showed elevated blood pressure and impaired endothelial vasorelaxation, whereas hypotensive effect of TSG was blunted. In co-culture system, TSG incubation promoted binding of peroxisome proliferator-activated receptor-γ (PPAR-γ) and Itln-1 promoter in adipocytes, activated Akt/eNOS/NO signaling and attenuated oxidative/nitrative stress in HUVECs. Suppression of Itln-1 with siRNA significantly blocked the protective effect of TSG in vitro.
Down-regulation of omentin-1 induces endothelial dysfunction and hypertension in obesity. TSG treatment (at least partially) increases omentin-1 via promoting binding of PPAR-γ and Itln-1 promoter in adipose tissues, subsequently exerts protective effects on endothelial function via activating Akt/eNOS/NO signaling and attenuating oxidative/nitrative stress. These results suggest that TSG could be developed as a promising anti-hypertension agent that protects against endothelial dysfunction and obesity-associated cardiovascular diseases.
肥胖相关性高血压已成为公共健康的主要威胁。内脂素-1 是一种新型脂肪因子，在肥胖症中表达下调。二苯乙烯苷（TSG）是从传统中药何首乌（PMT）中提取的主要成分，两千年来一直安全用于保护心血管系统。本研究旨在研究（i）内脂素-1 下调对肥胖相关高血压的影响及其潜在机制；（ii）二苯乙烯苷（TSG）是否通过增加内脂素-1 改善内皮功能障碍和肥胖相关高血压。
（TSG 处理）雄性 Zucker 糖尿病肥胖（ZDF）大鼠和内脂素-1 敲除（OMT）小鼠用于该研究。在体外，人脐静脉内皮细胞（HUVEC）和从人内脏前体脂肪细胞（HPA-v）分化而来的成熟脂肪细胞在共培养系统中维持。
TSG 是 PMT 的主要活性成分，可降低收缩压并改善内皮血管舒张。14 天 TSG 治疗（100mg/kg/天）增加了血清内脂素-1 水平，还激活了 Akt/eNOS 信号通路并增强了 NO 生物活性；降低了 NOX2 和 p22 的表达，抑制了超氧化物和过氧亚硝酸盐阴离子的产生。OMT 小鼠表现出血压升高和内皮血管舒张功能受损，而 TSG 的降压作用减弱。在共培养系统中，TSG 孵育促进了脂肪细胞中过氧化物酶体增殖物激活受体-γ（PPAR-γ）和 Itln-1 启动子的结合，激活了 Akt/eNOS/NO 信号通路，并减轻了 HUVECs 中的氧化/硝化应激。用 siRNA 抑制 Itln-1 可显著阻断 TSG 的体外保护作用。
内脂素-1 的下调会导致肥胖引起的内皮功能障碍和高血压。TSG 治疗（至少部分）通过促进脂肪组织中 PPAR-γ 和 Itln-1 启动子的结合增加内脂素-1 的表达，随后通过激活 Akt/eNOS/NO 信号通路和减轻氧化/硝化应激来发挥对内皮功能的保护作用。这些结果表明，TSG 可作为一种有前途的抗高血压药物开发，可预防内皮功能障碍和肥胖相关心血管疾病。
