Alpha-亚麻酸改善高血压前期的血管胰岛素抵抗从而延缓血压升高及其机制

There are about 41.3 persons in the stage of high-normal blood pressure in 100 Chinese, and the mobidity of hypertension is as high as 52.6% after 10 years among these people, so it may has significant value to make early intervention in the period of "prehypertension" to delay the development of hypertension. In our previous study, young spontaneously hypertensive rats (ySHR) with normal blood pressure exhibited significantly decreased aortic vasodilatation to insulin(Hypertension,2013), and improving vascular insulin resistance helps to limit the progression of hypertension(Am J Physiol Heart Circ Physiol,2013). This finding suggests that vascular insulin resistance(VIR) may play important roles in the development of hypertension. Clinical studies have demostrated that alpha linolenic acid (ALA) is beneficial for improving blood pressure, but its value in the period of prehypertension and underlying mechanism remain elusive. Our latest preliminary experiments demonstrated that feeding ALA improves VIR, deceases ENPP1expression, and reduces the blood pressure of ySHR. Based on these data, we hypothesized that ALA improves vascular insulin resistance by changing the expression of ENPP1 in SHRs. The aim of present study was to investigate whether feeding with ALA may mitigate hypertension by enhancing vascular insulin sensitivity. Clarifying this hypothesis mightgain further insight into the pathogenesis of hypertension and provide novel possibletargets for antihypertensive treatment.

国人的"高血压前期"发生率为41.3%，该人群10年后进展为临床高血压的比例高达52.6%，故将干预措施前移至高血压前期是有意义的预防策略。我们前期发现，血压正常的幼年自发性高血压大鼠（ySHR），即已存在胰岛素的舒血管效应减弱（血管胰岛素抵抗,VIR）（Hypertension,2013），而改善VIR可延缓血压增高(AJP-H&C,2013)，提示VIR促发血压升高的可能作用。临床研究表明α-亚麻酸(ALA)对改善血压有益，但其在高血压前期的效应及机制尚不清楚。我们新近预实验表明，ySHR摄食ALA可延缓血压升高、改善VIR，同时增加GalNAc-T2表达、减少ENPP1表达。据此假设，ALA可减少ENPP1表达、改善VIR，从而延缓血压升高。本项目拟用药理学与基因干预方法，研究ALA对VIR和动脉血压的影响及机制，为利用ALA指导大众健康、预防高血压的发生提供理论依据和治疗线索

国人的“高血压前期”发生率为41.3%，该人群10年后进展为临床高血压的比例高达52.6%，故将干预措施前移至高血压前期是有意义的预防策略。临床研究表明提示α-亚麻酸(alpha linolenic acid, ALA)有益于高血压患者，但其具体机制尚不清楚。我们的研究表明，对于SHR大鼠和AngII诱导高血压的小鼠，膳食补充ALA而非LA可改善高血压血管内皮功能障碍并降低血压，其机制与其改善血管胰岛素敏感性有关。血压正常的幼年自发性高血压大鼠（ySHRs）存在血管胰岛素抵抗；膳食补充ALA可促进ySHR大鼠血管内皮GalNAc-T2表达、抑制ENPP1表达，改善PI3K/Akt/eNOS/NO信号通路，进而改善高血压血管内皮胰岛素敏感性。此外，高血压状态下血管内皮SIRT3表达下调，内皮细胞自噬发生障碍，进而导致内皮氧化应激增加和血管功能障碍；而摄食ALA而非LA可上调内皮SIRT3水平，改善内皮自噬障碍，进而降低内皮氧化应激水平，最终改善高血压内皮功能障碍；对于SIRT3敲除小鼠， ALA裨益血管内皮、降低血压的作用消失。在本课题的资助下，投出SCI论文2篇 （Hypertension 2019；British Journal Of Pharmacology 2019），发表SCI论文4篇 (PLoS One. 2015; The American Journal of Chinese Medicine, 2016；Molecular Medicine Reports. 2016；Int. J. Med. Sci. 2018), 英文文章1篇，中文文章11篇，获得实用新型专利2项。培养研究生2名，课题负责人获得“陕西省科学技术二等奖”。