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

• 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
• 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

 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，但尚无可用的治疗方法。一个令人兴奋的可能性是，目前用于骨质疏松症的间歇性甲状旁腺激素 (iPTH) 治疗可能为 CAVD 提供治疗潜力，因为骨形成和 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 对既往患有 CAVD 的受试者的影响仍不清楚。由于 CAVD 广泛存在，尤其是在需要 iPTH 治疗的人群中普遍存在，因此确定 iPTH 对于那些已患有 CAVD 的人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 PTH 会促进骨骼骨形成。最近的进展表明 iPTH 和氧化应激之间存在意想不到的联系，氧化应激是 CAVD 的已知促成因素。其他人对成骨细胞的研究以及我们对血管平滑肌细胞 (VSMC) 的初步研究结果表明，iPTH 可以减少细胞氧化应激，这表明存在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，即在高脂血症小鼠中，iPTH 通过诱导血清对氧磷酶 1 (PON1) 活性来降低促炎性脂质氧化产物（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，我们假设，iPTH 会减弱先前存在的 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 PON1 间接降低氧脂的循环水平来实现这一点。我们提出 3 个目标。在目标 1 中，将在高脂血症小鼠中测试 iPTH 对先前存在的 CAVD 的影响。由于钙化斑块含有 iPTH 作用的两个潜在靶标：VSMC 和破骨前巨噬细胞，因此 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。我们将评估：1) 通过体内 18F™ microPET-microCT 成像评估主动脉钙沉积，该成像允许对个体小鼠进行连续扫描；2) 通过调节剂和标记物水平评估氧化应激以及骨软骨形成和破骨细胞分化。在目标 2 中，将确定 iPTH 的作用位点。将使用 PON1 缺陷型小鼠 (Pon1-/-ApoE-/-) 评估全身机制，并使用血管缺陷型 PTH 受体 1 小鼠 (Pth1rΔVSMCApoE-/-) 评估直接机制。在目标 3 中，我们将采用一种新型移植技术，将携带突变 1°鼠 VSMC 的扩散室皮下植入宿主小鼠体内，我们将测试：1）iPTH 与内源性 PTH 相关肽（PTHrP）对钙化的贡献，2）iPTH 在糖尿病低骨转换骨质疏松症中的作用。研究结果将揭示 iPTH 是否是一种治疗方法，或者是否会增加患有心血管疾病的患者患 CAVD 的风险，以及 iPTH 信号传导如何实现血管特异性效应。