Vitamin D Deficiency, Insulin Resistance and Cardiovascular disease

摘要 近一半的美国成年人患有高血压(HTN)，这是心血管疾病(CVD)的主要原因。HTN 在生命的早期发展有助于终末器官损伤的早期发展，从而增加 与较晚发病的HTN相比，心血管死亡的风险。多项研究提供了证据证明 假设子宫内的环境因素对胎儿和婴儿的生长模式产生影响 晚年对HTN的易感性增加。维生素D(VD)缺乏症在妊娠期和 与儿童时期HTN风险增加有关。我们之前发现巨噬细胞特异性 早期胚胎发育中VD受体的缺失通过两种机制诱导HTN：a)肾依赖 通过刺激miR106b的分泌来驱动JG细胞肾素的产生，以及b)通过 巨噬细胞肾素的产生和分泌增加。在啮齿动物模型中的更多研究支持 母体血管性痴呆在HTN发展中的缺陷和表观遗传机制的慢性炎症。在这 提案中，我们提供了初步数据，首次表明HTN可被免疫细胞移植。 宫内暴露于VD缺乏症的胎儿的造血干细胞(HSCs)可以永久移植 HTN给足够量的成年小鼠灌胃。维生素D缺乏表观遗传抑制Jarid2表达和 激活HSCs中的MEF2/Pgc1α通路，该通路持续存在于受者骨髓中，导致 巨噬细胞肾素和miR-106b的分泌，这两者都代表了免疫细胞通过 为HTN的发展贡献力量。在人类身上，我们发现导致HTN的免疫细胞程序是 在VDAART试验的儿童单核细胞中，可以通过产前补充4400 IU/天的VD来预防。 重要的是，补充了VD的母亲的孩子降低了臂部收缩压(BP)。 因此，我们假设，在怀孕早期补充VD可以防止Jarid2的表观遗传抑制 表达以避免肾素和miR106b从髓系细胞分泌的血压增加的影响。评估 这个表观免疫程序在体内，我们将利用HSC移植模型来确定在Aim1中是否1) Jarid2缺失足以诱导在子宫内VD缺乏症背景下观察到的HTN表型，2) MiR106b或肾素缺失可减弱与子宫内血管性痴呆相关的HTN表型 纠正妊娠早期的VD缺陷可防止后代发生HTN。在AIM2中，我们将 评估母亲补充VD对VDAART儿童血压和单核细胞的影响 Jarid2/PGC1miR106b/α/肾素/miR106b途径的激活及检测血浆miR106b和单核细胞RAS 激活是9-11岁儿童HTN的早期标志，来自一项随机对照试验(VDAART) 产前应用VD4400IU/d与安慰剂对照。这一建议将为母亲早期VD提供证据 筛查和治疗以降低儿童HTN的发病率并旨在建立miR106b作为一种 识别有心血管疾病风险的儿童的特定生物标志物。

ABSTRACT Nearly half of U.S adults have hypertension (HTN), a leading cause of the cardiovascular disease (CVD). HTN that develops earlier in life contributes to the early development of end-organ damage, thereby increasing the risk of cardiovascular mortality compared to later-onset HTN. Multiple studies provide evidence for the hypothesis that environmental factors in utero program patterns of fetal and infant growth that result in increased susceptibility to HTN later in life. Vitamin D (VD) deficiency is highly prevalent during pregnancy and has been linked to an increased risk of HTN during childhood. We previously found that macrophage-specific deletion of the VD receptor during early embryogenesis induced HTN by two mechanisms: a) renal-dependent by stimulating the secretion of miR106b to drive JG cell renin production and b) renal-independent by increased macrophage renin production and secretion. Additional studies in rodent models support the role of maternal VD deficiency in developing HTN and chronic inflammation via epigenetic mechanisms. In this proposal, we present preliminary data indicating for the first time that HTN is transplantable by immune cells. Hematopoietic stem cells (HSCs) from fetuses exposed to VD deficiency in utero can permanently transfer HTN to VD-sufficient adult mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1α pathway in HSCs, which persists in recipient bone marrow, resulting in macrophage renin and miR-106b secretion, both of which represent novel mechanisms by which immune cells contribute to the development of HTN. In humans, we found that this immune cells program causing HTN is preventable in children monocytes from the VDAART trial by antenatal 4400 IU/day of VD supplementation. Importantly, children from VD-supplemented mothers have decreased brachial-systolic blood pressure (BP). Thus, we hypothesize that VD supplementation early in pregnancy prevents epigenetic suppression of Jarid2 expression to avoid the BP-increasing effects of renin and miR106b secretion from myeloid cells. To evaluate this epigenetic immune program in vivo, we will utilize HSC transplantation models to determine in Aim1 if 1) Jarid2 deletion is sufficient to induce the HTN phenotype observed in the setting of in utero VD deficiency, 2) miR106b or renin deletion attenuates the HTN phenotype associated with in utero VD deficiency and 3) correction of VD deficiency early in pregnancy prevents the development of HTN in offspring. In Aim2, we will assess the role of maternal VD supplementation on VDAART children’s BP and monocyte Jarid2/PGC1α/Renin/miR106b pathway activation and determine if plasma miR106b and monocyte RAS activation are early markers of HTN in children at ages 9-11 from a randomized controlled trial (VDAART) of antenatal treatment with VD 4400 IU/d vs. placebo. This proposal will provide evidence for maternal early VD screening and treatment to decrease the incidence of childhood HTN and aim to establish miR106b as a specific biomarker identifying children at risk for CVD.