Mechanisms of intermittent parathyroid hormone effects on calcific aortic disease

间歇性甲状旁腺激素对钙化性主动脉疾病的作用机制

基本信息

批准号：
8880695
负责人：
Linda L. Demer
金额：
$ 38.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8880695
关键词：
Adult Age Amputation Animals Antioxidants Aortic Diseases Aortic Valve Stenosis Apolipoprotein E Arrhythmia Arteries Atherosclerosis Attenuated Blood Vessels Calcified Calcium Cardiovascular Diseases Cell Culture Techniques Chronic Kidney Failure Clinical Congestive Heart Failure Coronary Deposition Development Diabetes Mellitus Diet Diffusion Disease Estrogens Experimental Models Genetic Engineering Glucocorticoids Half-Life High Density Lipoproteins Hormonal Hormones Hyperlipidemia Hypertension Image Implant In Vitro Individual Infarction Inflammation Inflammatory Injection of therapeutic agent Ischemia Link Lipids Measures Mediating Mediator of activation protein Medical Minerals Morbidity - disease rate Mus Mutate Osteoblasts Osteogenesis Osteoporosis Paraoxonase 1 Parathyroid Hormone Receptor Parathyroid gland Patient Care Patients Plant Roots Population Postmenopausal Osteoporosis Prevalence Production Reactive Oxygen Species Receptor Activation Regimen Reporting Risk Scanning Serum Signal Transduction Site Skeletal bone Smooth Muscle Myocytes Techniques Testing Therapeutic Time Tissues Transplantation Vascular Diseases Ventricular Wit Work aortic valve apolipoprotein E-2 base bone bone loss bone turnover calcification cardiovascular risk factor cytokine high risk in vivo in vivo imaging innovation macrophage microCT microPET mineralization mortality mouse model mutant novel overexpression oxidant stress oxidation parathyroid hormone-related protein prevent public health relevance receptor research study

项目摘要

DESCRIPTION (provided by applicant): Calcific aortic vascular and valvular diseases (CAVD) carry a high mortality, yet no medical treatment is available. An exciting possibility is that intermittent parathyroid hormone (iPTH) treatment, currently used for osteoporosis, may offer therapeutic potential for CAVD, given that there is an age-independent, inverse relationship between bone formation and CAVD. Indeed, in an animal study, iPTH was found to prevent initiation of CAVD. However, the effect of iPTH in subjects with pre-existing CAVD is still not clear. Since CAVD is widespread and especially prevalent in the population requiring iPTH treatment, it is crucial to determine whether iPTH is still beneficial or even harmful in those wit pre-existing CAVD. Of note, in contrast to continuously high serum PTH levels, which promote bone loss and CAVD, intermittently high levels produced by daily injection of PTH, promote skeletal bone formation. Recent developments suggest an unexpected link between iPTH and oxidant stress, a known contributor of CAVD. Studies by others in osteoblasts and our preliminary findings in vascular smooth muscle cells (VSMC) show that iPTH reduced cellular oxidant stress, suggesting a direct receptor-mediated mechanism. A second mechanism is also suggested by our recent report showing that, in hyperlipidemic mice, iPTH reduces circulating levels of proinflammatory lipid oxidation products (oxylipids) by inducing serum paraoxonase-1 (PON1) activity. Based on these findings and our previous work showing that oxylipids promote CAVD, we hypothesize that, iPTH will attenuate pre-existing CAVD and will do so, in part, directly by reducing levels of cellular oxidant stress and, in part, indirectly by reducing circulaing levels of oxylipids via PON1. We propose 3 Aims. In Aim 1, iPTH effects will be tested on pre-existing CAVD in hyperlipidemic mice. Since calcific plaque contains two potential targets of iPTH action, VSMC and preosteoclastic macrophages, iPTH may attenuate CAVD by inhibiting osteochondrogenic differentiation and/or by inducing mineral resorption. We will assess: 1) aortic calcium deposition by in vivo 18F¯ microPET-microCT imaging, which allows serial scanning of individual mice and 2) oxidant stress and osteochondrogenic and osteoclastic differentiation by levels of regulators and markers. In Aim 2, the iPTH sites of action will be determined. The systemic mechanism will be assessed using PON1- deficient mice (Pon1-/-ApoE-/-), and the direct mechanism will be assessed using vascular deficient PTH receptor 1 mice (Pth1rΔVSMCApoE-/-). In Aim 3, we will employ a novel transplant technique, in which diffusion chambers carrying mutated 1°murine VSMC will be implanted subcutaneously into host mice, and we will test: 1) contributions of iPTH vs. endogenous PTH-related peptide (PTHrP) on calcification and 2) effects of iPTH in the context of low bone turnover osteoporosis of diabetes. The findings will reveal whether iPTH is a treatment or a risk for CAVD in patients with pre-existing cardiovascular disease, and how iPTH signaling achieves vascular-specific effects.

描述（由申请人提供）：钙化性主动脉血管和瓣膜疾病（CAVD）死亡率很高，但目前尚无可用的医学治疗方法，目前用于治疗骨质疏松症的间歇性甲状旁腺激素（iPTH）治疗可能具有治疗潜力。对于 CAVD，鉴于骨形成和 CAVD 之间存在与年龄无关的负相关关系，事实上，在一项动物研究中，发现 iPTH 可以预防 CAVD 的发生。然而，iPTH 对已患有 CAVD 的受试者的影响仍不清楚，因为 CAVD 广泛存在，并且在需要 iPTH 治疗的人群中尤其普遍，因此确定 iPTH 对那些患有 CAVD 的患者是否仍然有益甚至有害至关重要。值得注意的是，与会促进骨质流失和 CAVD 的持续高血清 PTH 水平相反，每天注射 PTH 产生的间歇性高水平会促进骨骼骨形成。 iPTH 和氧化应激之间的联系是 CAVD 的已知因素。其他人对成骨细胞的研究以及我们在血管平滑肌细胞 (VSMC) 中的初步发现表明，iPTH 可以减少细胞氧化应激，这表明第二种机制是直接受体介导的。我们最近的报告也表明，在高脂血症小鼠中，iPTH 通过诱导血清对氧磷酶-1 (PON1) 降低促炎脂质氧化产物（氧脂）的循环水平基于这些发现和我们之前的工作表明，氧脂会促进 CAVD，我们认为，iPTH 将减弱先前存在的 CAVD，并且部分是通过直接降低细胞氧化应激水平来实现这一点，部分是通过间接地通过降低细胞氧化应激水平来实现这一点。通过 PON1 降低循环脂类水平在目标 1 中，将在高脂血症小鼠中测试 iPTH 的效果。钙化斑块含有 iPTH 作用的两个潜在靶标，即 VSMC 和破骨细胞前巨噬细胞，iPTH 可能通过抑制骨软骨分化和/或诱导矿物质吸收来减弱 CAVD。我们将通过体内 18F™ microPET-microCT 成像评估主动脉钙沉积，允许对个体小鼠进行连续扫描，2）通过调节剂水平进行氧化应激以及骨软骨形成和破骨细胞分化在目标 2 中，将使用 PON1 缺陷小鼠 (Pon1-/-ApoE-/-) 确定 iPTH 作用位点，并使用血管缺陷 PTH 受体 1 评估直接机制。小鼠 (Pth1rΔVSMCApoE-/-) 在目标 3 中，我们将采用一种新颖的移植技术，其中携带突变的 1°鼠 VSMC 的扩散室将被皮下植入。进入宿主小鼠，我们将测试：1）iPTH 与内源性 PTH 相关肽（PTHrP）对钙化的贡献以及 2）iPTH 在糖尿病低骨转换骨质疏松症中的作用。这些研究结果将揭示 iPTH 是否是钙化的影响。既往患有心血管疾病的患者的 CAVD 治疗或风险，以及 iPTH 信号如何实现血管特异性效应。