Jin Jiaqi, Liu Jingya, Luo Yong, He Hong, Zheng Xinyue, Zheng Chaoyang, Huang Yi, Chen Yang
School of Pharmaceutical, Guangzhou University of Chinese Medicine, No. 232 Waihuan Dong Rd., Guangzhou University Town, Panyu District, Guangzhou, 510000, China.
Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, No. 63 Duobao Road, Liwan District, Guangzhou, 510150, China.
Nutr Metab (Lond). 2022 Mar 24;19(1):24. doi: 10.1186/s12986-022-00659-3.
Processed foods are popular and contain large amounts of industrial fructose, which changes people's diet and exacerbates the negative health effects of high fructose. Several studies have shown that excessive intake of fructose has a major impact on vascular disease. However, the mechanism of the effect of high fructose on blood vessels is currently unclear.
The effect of fructose on the vasodilatation of isolated thoracic aortic rings was observed by using wire myography in wild-type (WT) mice. Cell viability and nitric oxide (NO) production were assessed by the corresponding kits in mouse vascular endothelial cells. The effect of fructose on endothelial nitric oxide synthase (eNOS) and protein phosphatase 2A (PP2A) and their changes in phosphorylation were detected by using Western blots. Moreover, a PP2A inhibitor (okadaic acid, OA) was used to evaluate the relationship between fructose and PP2A. Furthermore, PP2ACα endothelial-specific knockout (PP2A cKO) mice were used to detect the vasodilatation of in vitro fructose-incubated thoracic aortic rings by using wire myography.
High fructose induced endothelium-dependent dysfunctional vasodilatation. High fructose reduced acetylcholine (Ach)-induced vasodilation but did not affect sodium nitroprusside (SNP)-induced vasodilation. Accordingly, NO production and the phosphorylation level of eNOS at serine (Ser) 1177 (P-eNOS) in vascular endothelial cells were remarkably reduced without changes in cell viability. The expression of protein phosphatase 2A catalytic subunit (PP2AC) was increased and the expression of phosphorylated PP2AC (P-PP2A, tyrosine [Tyr] 307) was significantly decreased. Nevertheless, these effects were reversed by OA. Moreover, knockout of the PP2A gene could recover the response of vessels to Ach under high fructose stimulation.
Our observations demonstrate an underlying mechanism of fructose-induced dysfunctional vasodilatation. Fructose could activate PP2A, which leads to decrease in the phosphorylation of eNOS at Ser1177 and the reduction of NO release, thus leading to the occurrence of endothelium-dependent dysfunctional vasodilatation.
加工食品很受欢迎，且含有大量工业果糖，这改变了人们的饮食结构，并加剧了高果糖对健康的负面影响。多项研究表明，过量摄入果糖对血管疾病有重大影响。然而，高果糖对血管产生影响的机制目前尚不清楚。
利用线肌张力测定法在野生型（WT）小鼠中观察果糖对离体胸主动脉环舒张的影响。通过相应试剂盒评估小鼠血管内皮细胞的细胞活力和一氧化氮（NO）生成量。利用蛋白质免疫印迹法检测果糖对内皮型一氧化氮合酶（eNOS）和蛋白磷酸酶2A（PP2A）及其磷酸化变化的影响。此外，使用PP2A抑制剂（冈田酸，OA）来评估果糖与PP2A之间的关系。此外，利用PP2ACα内皮特异性敲除（PP2A cKO）小鼠，通过线肌张力测定法检测体外果糖孵育的胸主动脉环的舒张情况。
高果糖诱导内皮依赖性舒张功能障碍。高果糖降低了乙酰胆碱（Ach）诱导的血管舒张，但不影响硝普钠（SNP）诱导的血管舒张。相应地，血管内皮细胞中NO生成量以及eNOS丝氨酸（Ser）1177位点的磷酸化水平（P-eNOS）显著降低，而细胞活力无变化。蛋白磷酸酶2A催化亚基（PP2AC）的表达增加，磷酸化PP2AC（P-PP2A，酪氨酸（Tyr）307）的表达显著降低。然而，这些效应被OA逆转。此外，敲除PP2A基因可恢复高果糖刺激下血管对Ach的反应。
我们的观察结果揭示了果糖诱导舒张功能障碍的潜在机制。果糖可激活PP2A，导致eNOS在Ser1177位点的磷酸化减少以及NO释放降低，从而导致内皮依赖性舒张功能障碍的发生。
