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（由适用提供）：钙化主动脉血管和瓣膜疾病（CAVD）具有高死亡率，但没有治疗。一个令人兴奋的可能性是，鉴于骨形成与CAVD之间存在无关年龄的，与年龄无关的，无关的，骨的关系，目前用于骨质疏松症的间歇性甲状旁腺（IPTH）治疗可能为CAVD提供治疗潜力。实际上，在一项动物研究中，发现IPTH可以防止CAVD的倡议。但是，IPTH在先前存在的CAVD受试者中的影响尚不清楚。由于CAVD是普遍存在的，尤其是在需要IPTH治疗的人群中尤其普遍，因此确定IPTH在那些现有的CAVD中是否仍然是有益甚至有害的至关重要的。值得注意的是，与持续高的血清PTH水平相比，促进骨质流失和CAVD的水平是间歇性高水平，每天注射PTH会促进骨骼骨骼形成。最近的发展表明，IPTH和氧化物应激之间存在意外的联系，这是CAVD的已知贡献者。其他人在成骨细胞中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减少了细胞氧化物的胁迫，表明直接受体介导的机制。我们最近的报告还提出了第二种机制，表明，在高脂小鼠中，IPTH通过诱导血清偏氧蛋白酶1（PON1）活性来降低促炎性脂质氧化产物（氧化磷脂）的循环水平。基于这些发现和我们先前的工作表明氧基促进了CAVD，我们假设，IPTH会减弱先前存在的CAVD，并部分直接通过通过PON1降低氧化物水平来直接降低细胞氧化物应激水平，部分地通过降低氧化脂质的水平而降低。我们提出了3个目标。在AIM 1中，将对高脂小鼠预先存在的CAVD进行IPTH效应。由于钙化斑块包含IPTH作用的两个潜在靶标，VSMC和骨塑性巨噬细胞可能会通过抑制骨软骨变化和/或通过诱导的矿物分辨率来减弱CAVD。我们将评估：1）体内18F微型钙 - 微切成像的主动脉钙沉积，该成像允许在AIM 3中进行连续扫描，我们将采用一种新颖的移植，一种新颖的移植，一种新颖的移植，一种新颖的机制（PTH1RΔVSMCAPOE--/ - ）。其中携带突变1°鼠VSMC的扩散室将皮下植入宿主小鼠中，我们将测试：1）IPTH与内源性PTH相关肽（PTHRP）对钙化和2个对2）影响的贡献。这些发现将揭示IPTH是一种治疗的心脏血管疾病患者的治疗或CAVD的风险，以及IPTH信号传导如何实现血管特异性作用。