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

项目概要/摘要 血管钙化，特别是冠状动脉钙化（CAC），与以下风险增加相关： 心血管疾病，而定期的身体活动与降低风险有关。因此， 预测身体活跃的人会有更少的CAC，但临床研究显示相反。精英 运动员实际上比久坐的运动员有更多的CAC，即使他们有更低的心脏事件 rates.本建议的目的是确定这种矛盾的机制。临床研究表明 含有大量连续钙沉积的冠状动脉斑块与心血管疾病 风险比碎片钙沉积，一种可能性是，运动重塑钙沉积成一个 更稳定的微架构。理论分析模型还预测， 预期钙沉积可降低斑块破裂风险。有趣的是，人类的一次运动 和小鼠引起甲状旁腺激素（PTH）短暂升高1.8倍， 人类和小鼠中的PTH导致骨生长增加，这与血管紧张素转换酶的信号传导机制相同。 钙化我们最近的研究结果提供了PTH和血管微结构之间的联系， 钙沉积，其中间歇性PTH治疗减少了主动脉钙沉积的表面积， 预先存在血管钙化的高脂血症小鼠。我们的初步研究提供了更直接的 运动与血管钙沉积重塑的关系。我们发现高脂血症小鼠 预先存在主动脉钙化的患者接受9周的跑步机治疗方案，血清PTH水平升高， 主动脉根部的PTH受体水平，核成像显示矿物质表面积减少， 组织形态计量学因此，我们假设运动通过激活血管PTH 1受体， 使钙沉积物的微结构向更稳定的形式转变，降低破裂风险。我们 将使用3个特定目的来检验我们的假设，以确定：1）PTH 1受体活化的丧失是否 阻断运动诱导的血管钙沉积的重塑; 2）循环的相对贡献 甲状旁腺素和局部（组织）甲状旁腺素相关肽（PTHrP）对运动性微结构变化的影响; 混杂因素（性别、运动剂量、饮食和物种）对运动诱导的 SMC转录组和血管钙存款微结构。我们将使用药理学，遗传学， 和手术模型，终点将包括主动脉钙的进展和微结构 沉积物，包括基于结构分析的尺寸和表面积（系列18 F-µPET/µCT， 组织形态学）、转录组分析和使用球囊导管作为 一个机械传感器的破裂脆弱性。这项拟议中的研究意义重大，因为它将决定 高强度运动引起的血管钙化增加是保护性的还是有害的， 可以通过调节PTH受体活化来控制。

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.