Role of intermittent activation of parathyroid hormone receptor in exercise-induced vascular calcification

甲状旁腺激素受体间歇性激活在运动性血管钙化中的作用

• 批准号: 10320968
• 负责人: Linda L. Demer
• 金额: $ 55.29万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320968
• 关键词: Area; Arteries; Athletic; Blood Vessels; Bone Growth; Calcium; Cardiac; Cardiovascular Diseases; Cardiovascular system; Catheters; Cholesterol; Clinical; Clinical Research; Deposition; Diet; Dose; Equilibrium; Event; Exercise; Face; Female; Fluorides; Genetic Models; Genetic Transcription; Health Status; Hormone Antagonists; Hormone Receptor; Human; Hyperlipidemia; Image; Immunohistochemistry; Individual; Injections; Label; Lesion; Link; Measures; Mechanics; Minerals; Modeling; Morbidity - disease rate; Morphology; Mus; PTH gene; Parathyroid Hormone Receptor; Parathyroidectomy; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Physical activity; Plant Roots; Porosity; Positron-Emission Tomography; Public Health; Receptor Activation; Regimen; Regulation; Research; Risk; Role; Rupture; Serum; Signal Transduction; Smooth Muscle Myocytes; Strenuous Exercise; Stress; Surface; Surgical Models; Testing; Tissues; Up-Regulation; Vascular Smooth Muscle; Vascular calcification; Vascular remodeling; base; biomechanical test; calcification; cardiovascular disorder risk; cardiovascular risk factor; coronary artery calcification; coronary plaque; density; exercise capacity; experience; genome wide screen; high risk; improved; in vivo; male; mortality; mouse model; novel; nuclear imaging; parathyroid hormone-related protein; predictive modeling; receptor expression; response; sedentary; sensor; sex; transcriptome; treadmill; uptake

PROJECT SUMMARY/ABSTRACT Vascular calcification, especially coronary artery calcification (CAC), is associated with increased risk of cardiovascular disease, whereas regular physical activity is associated with decreased risk. Thus, one would predict that physically active individuals would have less CAC, yet clinical studies show the opposite. Elite athletes actually have more CAC than their sedentary counterparts even though they have lower cardiac event rates. The objective of this proposal is to determine the mechanism of this paradox. As clinical studies show that coronary plaques containing large, contiguous calcium deposits are associated with less cardiovascular risk than fragmented calcium deposits, one possibility would be that exercise remodels calcium deposits into a more stable microarchitecture. Theoretical analytical modeling also predicts that decreased surface area of calcium deposits is expected to reduce plaque rupture risk. Interestingly, a single bout of exercise in humans and mice causes a transient 1.8-fold elevation of parathyroid hormone (PTH), and intermittent treatment of PTH in humans and mice causes increased bone growth, which shares signaling mechanisms with vascular calcification. Our recent findings provide an association between PTH and microarchitecture of vascular calcium deposits, where intermittent PTH treatment reduces the surface area of aortic calcium deposits in hyperlipidemic mice with pre-existing vascular calcification. Our preliminary studies provide a more direct association of exercise with the remodeling of vascular calcium deposits. We found that hyperlipidemic mice with pre-existing aortic calcification on a 9-week treadmill regimen had increased serum PTH levels, increased PTH receptor levels in the aortic roots, and decreased mineral surface area by nuclear imaging and histomorphometry. Thus, we hypothesize that exercise, through activation of the vascular PTH1 receptor, shifts the microarchitecture of calcium deposits toward a more stabilized form, reducing the rupture risk. We will test our hypothesis using 3 Specific Aims to determine: 1) whether loss of PTH1 receptor activation blocks the exercise-induced remodeling of vascular calcium deposits; 2) the relative contributions of circulating PTH and local (tissue) PTH related peptide (PTHrP) on the exercise-induced changes in microarchitecture; and 3) effects of confounding factors (sex, exercise dose, diet, and species) on exercise-induced changes in the SMC transcriptome and vascular calcium deposit microarchitecture. We will use pharmacologic, genetic, and surgical models, and the endpoints will include progression and microarchitecture of aortic calcium deposits, including size and surface area based on structural analyses (serial 18F-µPET/µCT, histomorphometry), transcriptome analysis, and functional biomechanical analyses using a balloon catheter as a mechanical sensor for rupture vulnerability. The proposed research is significant because it will determine whether increased vascular calcification with intense exercise is protective or harmful and whether the effects can be controlled by modulating PTH receptor activation.

项目摘要/摘要 血管钙化，尤其是冠状动脉动脉钙化（CAC），与INCRED风险相结合 心血管疾病，而定期的体育活动与降低风险有关 预测物理活跃的个体的CAC较少，但临床研究表明了相反的情况。 实际上，运动员的CAC比久坐的贵族甚至有较低的心脏事件 该提案的目的是确定该悖论的机制。 冠状斑块含有大的连续钙沉积物与心血管较少有关 风险比碎片钙沉积物的风险，一种可能性是锻炼钙沉积 更稳定的微体系结构。 钙沉积物期望降低斑块的风险。 小鼠会导致甲状旁腺激素（PTH）的升高1.8倍，并进行了内在治疗 人类和小鼠的PTH会导致骨骼生长增加，该骨骼的生长是用Vascalar发出的。 钙化。 钙沉积物，间歇性PTH处理减少了主动脉钙沉积的表面积 高脂小鼠具有先前存在的血管钙化。 运动与血管钙沉积物的重塑相关联。 在9周的跑步机方案上先前存在的主动脉钙化的血清PTH水平升高，增加 主动脉根中的PTH受体水平，并通过核成像和 因此，我们通过激活血管PTH1受体来假设该运动 将钙沉积物的微体系结构转移到更稳定的形式，从而降低了我们的风险 将使用3个特定目的来测试我们的假设：1）PTH1受体激活是否丧失 阻止锻炼诱导的血管钙沉积物的重塑； 2）循环的相对贡献 PTH和局部（组织）PTH相关的肽（PTHRP）在运动引起的微体系结构变化上； 3）混杂因素（性别，运动剂量，饮食和物种）对运动引起的变化的影响 SMC转录和血管沉积微体系结构。 和手术模型，终点将包括主动脉caltic caltic caltic caltic caltic caltic caltic caltic calticuum 基于结构分析（串行18F µPET/µCT），沉积物，包含大小和表面积 组织形态计量学），转录组分析和功能性生物力学分析，使用球囊导管作为 破裂脆弱性的机械传感器。 是否通过强度运动增加血管钙化是保护器还是危害，以及影响 可以通过调节PTH受体激活来控制。