维生素A营养对儿童高血压患病风险的作用及机制研究

Essential hypertension (EH) is one of the major diseases endangering human health, which is the focus of medical research. Studies have shown that EH is affected by both environmental and genetic factors. Our research group found the relevance between serum levels of vitamin A (VA) and EH by population-based study. VA deficiency increases the risk of EH, and supplementing VA can decrease the blood pressure of SHR. The possible mechanism is that VA inhibits the activity of AngⅡ through nuclear receptors (RAR / RXR) , decreases its binding with angiotensin type 1 receptor (AT1R), and restrains vascular smooth muscle cell proliferation and sodium and water reabsorption, and thus plays a role in blood pressure controlling and vascular protection. But there is no definite conclusion about what is the connection between VA and blood pressure among hypertensive children, whether randomized controlled intervention trials of VA supplement can produce antihypertensive effect, and how VA regulates blood pressure by AngⅡ regulatory pathways. Therefore, this study intends to start from solving clinical problems. Firstly, the relationship between VA and blood pressure will be analyzed through the data of large population sample. Secondly, the antihypertensive effect of supplementing VA and the relationship between blood pressure and VA , AngⅡ will be discovered through randomized controlled intervention trials of supplementing VA to 600 hypertension children, and the mechanism of controlling blood pressure through suppressing AngⅡ by VA will be further clarified. This study aims to reveal the antihypertensive effect of supplementing VA appropriately to EH patients and its mechanism, and provide a new way to prevent and treat EH.

原发性高血压（EH）是严重危害人类健康的重大疾病，是医疗卫生行业研究的重点。本课题组人群研究发现血清维生素A水平（VA）与EH存在相关性，VA缺乏将增加EH发病风险，动物实验表明VA补充能产生有效的降压作用，其机制可能是VA通过其核受体RAR/RXR抑制血管紧张素Ⅱ（AngⅡ）的活性，减少其与血管紧张素Ⅱ1型受体结合，抑制血管平滑肌细胞增生与水钠重吸收，从而发挥降压与血管保护作用。但在高血压儿童人群中VA与血压的关系如何，进行VA补充的随机对照干预试验能否产生有效的降压作用，VA如何通过AngⅡ代谢通路调节血压，目前均未见明确的研究结论。因此，本课题拟从解决临床问题出发，首先，通过大样本人群数据分析VA与血压间的关系；其次，通过对600例高血压儿童补充VA的随机对照干预试验，探明VA补充的降压效果及VA、AngⅡ与血压间的关系，并进一步探讨VA通过抑制AngⅡ调控血压的机制。

本研究包括儿童高血压病例对照研究及动物实验的随机对照干预研究.第一部分 维生素A与儿童高血压相关性的病例对照研究.目的：维生素A与儿童血压之间的相关关系。.方法:在前期已建立的儿童队列人群中纳入高血压儿童8O例与正常血压儿童84人进行病例对照研究，采集受试对象的静脉血完成血生化及基因检测，对受试对象进行体格检查与问卷调查。.结果:高血压与正常血压儿童血清维生素A水平差异无统计学意义[(O.87±0.22)比(0.89±0.23)μmol/L，P=0.56]。高血压组中，维生素A缺乏组收缩压与舒张压高于维生素A正常组[(133.4±1.7)比(127.1±0.7)mm Hg；(78.0±1.9)比(75.4土0.8)mm Hg；P<0.01]；在对照组中，维生素A缺乏组儿童收缩压高于维生素A正常组[(105.6±1.3)比(100.4±0.8)mm Hg，P<O.01]，舒张压差异无统计学意义(P>O.05)。聚合酶链反应结果显示，维甲酸受体(RAR)在两组间差异无统计学意义，但反映维生素A贮存功能的指标卵磷脂视黄醇酰基转移酶(LRAT)在高血压组低于对照组(P<O.01)。.结论:维生素A在体内的储存水平低是高血压的危险因素，VA的缺乏将进一步加重高血压的进程。..第二部分 维生素A缺乏对自发性高血压大鼠（SHR）血压及心室重塑的影响.目的：探讨维生素A 缺乏对RAS生物标记水平，血压与心肌结构的损害。.方法：对原发性高血压大鼠与Wistar大鼠，进行维生素A缺乏（VAD）与维生素A正常（VAN）饲料进行干预20周。.结果：采用VAD饲料干预动物的收缩压，舒张压与平均动脉压水平显著增高，而血清及肝脏视黄醇水平显著降低。与VAN干预的高血压大鼠比较，VAD干预的高血压大鼠Ang II与BNP水平显著的增加，导致ACE与AT1R水平的增加，视黄酸受体(RARα), 视黄醇酰基转移酶 (LRAT), ACE2与 Ang (1-7)蛋白表达水平上升,同时VAD干预的高血压大鼠的ACE与 AT1R表达水平上升。除此以外，VAD干预的高血压大鼠的心脏体重、左心室体重、心脏重量与体重比值，左心室重量与体重的比值均显著性的高于VAN干预的高血压大鼠。.结论：血清与组织器官中维生素A缺乏，RARα与LRAT表达水平的降低，将导致ACE, AT1R, Ang II与BNP水平的上调，及