Role of Lymphatic Clearance in Lipid-Induced Calcific Vasculopathy and Bone Loss

淋巴清除在脂质引起的钙化性血管病和骨丢失中的作用

• 批准号: 8165115
• 负责人: Linda L. Demer
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165115
• 关键词: Aerobic; Agitation; American; Antioxidants; Area; Arteries; Atherosclerosis; Behavior; Blood; Blood Circulation; Blood capillaries; Bone Diseases; Breathing; Cardiovascular Diseases; Cardiovascular system; Chronic; Clinical; Complement; Deposition; Diet; Disease; Duct (organ) structure; Epitopes; Feeds; Frequencies; Heart Diseases; Hyperlipidemia; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Lead; Life Style; Lipids; Lipoproteins; Liquid substance; Liver; Liver Circulation; Lung; Lymphatic; Lymphatic Capillaries; Lymphatic vessel; Mechanical Stress; Mechanics; Modification; Molecular; Morbidity - disease rate; Mus; Muscle Contraction; Myocardial Infarction; Osteitis; Osteoporosis; Pathogenesis; Physical activity; Physiological; Pilot Projects; Prevention; Production; Pump; Research; Role; Sedation procedure; Series; Signal Transduction; Skeletal Muscle; Sturnus vulgaris; Testing; Therapeutic; Therapeutic Intervention; Thoracic Duct; Thoracic cavity structure; Time; Tissues; Translating; Vascular Diseases; Vascular calcification; Venous; Work; behavioral impairment; bone; bone loss; capillary; falls; glycation; improved; in vivo; interstitial; lipoprotein cholesterol; lymphatic circulation; mortality; mouse model; novel; oxidation; oxidized lipid; pressure; prevent; residence; reverse cholesterol transport; sedative; sedentary; vascular inflammation

DESCRIPTION (provided by applicant): Atherosclerosis remains a major cause of morbidity and mortality despite substantial therapeutic interventions. Evidence suggests that the ever-more sedentary lifestyle of Americans is undermining the benefits of lipid- lowering therapy. It is widely accepted that tissue deposition and modification of lipoproteins induce inflammation and atherosclerosis; we and others are now showing that the same mechanism underlies vascular calcification and bone loss. It is well known that the interstitial spaces of tissues are normally cleared by fluid circulation through the lymphatic circulatory system, and that lymphatic circulation, which has no pump, depends on physical activity. Interestingly, cardiovascular disease is reduced by even mild physical activity -- below levels that promote aerobic capacity -- through mechanisms that are not known. One promising area of atherosclerosis research is reverse cholesterol transport, which focuses on removing lipoprotein deposits from the interstitial spaces of the artery wall to the circulation for hepatic clearance. However, if sedentary behavior impairs lymphatic circulation, enhancing reverse cholesterol transport at the molecular level may not translate to clinical benefit. Integrative physiological approaches are needed to complement the current molecular approach to reverse cholesterol transport. We hypothesize that enhancing lymphatic clearance reduces stagnation of lipoproteins in the interstitial spaces and prevents vascular and bone inflammation and disease. To test this novel hypothesis, we will develop interventions to maximize and minimize lymphatic flow in a mouse model of atherosclerosis and osteoporosis. We will use three interventions to induce changes in lymphatic clearance in mice: 1) Lyve1 deficiency, which enhances baseline lymphatic circulation, 2) controlled physical activity, to increase lymphatic flow, and 3) sedatives to reduce lymphatic flow. In Specific Aim 1, we will explore the effects of maximal vs. minimal lymphatic clearance on vascular disease using diet-induced atherosclerosis and vascular calcification in hyperlipidemic mice. In Specific Aim 2, we will explore the effects of maximal vs. minimal lymphatic clearance on bone disease using diet-induced osteoporosis in hyperlipidemic mice. In this pilot study, we will explore the levels of frequency and intensity of activity required to induce lymphatic flow, and test whether maximizing lymphatic circulation prevents vascular and bone disease. Findings of this work could introduce a promising new direction of research and greatly benefit prevention and treatment of atherosclerosis and osteoporosis. PUBLIC HEALTH RELEVANCE: Prolonged sedentary behavior, which leads to poor lymphatic clearance, may be a key mechanism for accumulation and oxidation of lipids in the artery wall and even in bone. Lymphatic circulation is needed to clear inflammatory and oxidized lipids, but it fails without physical activity. This study will test whether promoting lymphatic clearance by physical activity can prevent chronic inflammatory diseases of the heart and bone such as atherosclerosis and osteoporosis.

描述（由申请方提供）：尽管进行了大量的治疗干预，但动脉粥样硬化仍然是发病率和死亡率的主要原因。有证据表明，美国人越来越多的久坐不动的生活方式正在破坏降脂治疗的益处。组织沉积和脂蛋白的修饰诱导炎症和动脉粥样硬化已被广泛接受;我们和其他人现在表明，血管钙化和骨丢失的基础是相同的机制。众所周知，组织的间隙空间通常由通过淋巴循环系统的流体循环来清除，并且没有泵的淋巴循环依赖于身体活动。有趣的是，即使是轻微的身体活动也能减少心血管疾病-低于促进有氧能力的水平-通过未知的机制。动脉粥样硬化研究的一个有前途的领域是胆固醇逆向转运，其重点是将脂蛋白沉积物从动脉壁的间隙空间移到循环中以供肝脏清除。然而，如果久坐行为损害淋巴循环，在分子水平上增强胆固醇的逆向转运可能不会转化为临床益处。需要综合的生理学方法来补充目前逆转胆固醇转运的分子方法。我们推测，增强淋巴清除减少了脂蛋白在间质空间的停滞，并防止血管和骨骼炎症和疾病。为了验证这一新的假设，我们将在动脉粥样硬化和骨质疏松症的小鼠模型中开发干预措施，以最大化和最小化淋巴流量。我们将使用三种干预措施来诱导小鼠淋巴清除的变化：1）Lyve 1缺乏，这会增强基线淋巴循环，2）控制体力活动，以增加淋巴流量，3）镇静剂，以减少淋巴流量。在具体目标1中，我们将在高脂血症小鼠中使用饮食诱导的动脉粥样硬化和血管钙化来探索最大与最小淋巴清除对血管疾病的影响。在具体目标2中，我们将在高脂血症小鼠中使用饮食诱导的骨质疏松症来探索最大与最小淋巴清除对骨疾病的影响。在这项初步研究中，我们将探索诱导淋巴流动所需的活动频率和强度水平，并测试最大化淋巴循环是否可以预防血管和骨骼疾病。本研究为动脉粥样硬化和骨质疏松症的防治提供了新的研究方向。 公共卫生关系：长时间的久坐行为导致淋巴清除不良，这可能是动脉壁甚至骨骼中脂质积累和氧化的关键机制。淋巴循环需要清除炎症和氧化脂质，但如果没有身体活动，它就会失败。这项研究将测试通过体育活动促进淋巴清除是否可以预防心脏和骨骼的慢性炎症性疾病，如动脉粥样硬化和骨质疏松症。