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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘