Hypercholesterolemia in Cardiac Function, Survival and Repair

高胆固醇血症对心脏功能、存活和修复的影响

• 批准号: 7583039
• 负责人: GREGG ROKOSH
• 金额: $ 33.3万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7583039
• 关键词: Acute; Address; Adult; Affect; Animal Model; Animals; Arterial Fatty Streak; Atherosclerosis; Biochemical; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular Physiology; Catheterization; Caveolae; Cell Communication; Cell Therapy; Cell physiology; Cells; Cholesterol; Chronic; Clinic; Clinical; Clinical Trials; Complex; Confocal Microscopy; Coronary Occlusions; Data; Development; Diabetes Mellitus; Diet; Dose; EFRAC; Echocardiography; Endoplasmic Reticulum; Engraftment; Evaluation; Experimental Models; Family suidae; Funding; Goals; Heart; Heart failure; Homing; Human; Hypertension; Immunohistochemistry; In Vitro; Infarction; Injury; Integrins; Ischemic Preconditioning; LDL Cholesterol Lipoproteins; Light; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Matrix Metalloproteinases; Measures; Mediating; Membrane Microdomains; Modeling; Molecular Biology; Morphology; Motion; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial perfusion; Myocardial tissue; Myocardium; Natural regeneration; Outcome; Paracrine Communication; Pathology; Patients; Performance; Physiology; Plasma; Population; Preparation; Process; Proteins; Rattus; Reperfusion Therapy; Research; Risk; Risk Factors; Role; Signal Transduction; Specimen; Stem cells; Stromal Cell-Derived Factor 1; Structure; Testing; Tissue Extracts; Tissues; Transplanted tissue; Work; base; biological adaptation to stress; biological systems; cardiovascular risk factor; cell type; endoplasmic reticulum stress; extracellular; feeding; hemodynamics; hypercholesterolemia; improved; in vitro testing; in vivo; insight; interdisciplinary approach; interest; low density lipoprotein inhibitor; migration; modifiable risk; novel; oxidation; pre-clinical; preconditioning; pressure; primitive cell; programs; public health relevance; reconstitution; repaired; research study; response; stem; stem cell therapy; translational study

DESCRIPTION (provided by applicant): Mounting mechanistic and translational studies support the use of cell-based therapies to repair myocardial tissue destroyed by infarction and to restore cardiac function. Several phenotypically distinct subsets of adult primitive cell populations have been shown to improve cardiac structure and function in animal models of myocardial infarction (MI) and heart failure. Small clinical trials of stem cell therapy have recapitulated these beneficial effects in patients with ischemic cardiomyopathy. Recent discovery of cardiac stem cells (CSCs) has sparked intense hope for the development of promising stem cell therapies for cardiac repair/regeneration because CSCs are inherently programmed to reconstitute cardiac tissue. In recent studies, we found that intracoronary delivery of CSCs to rats with either acute or chronic MI and to pigs with chronic MI ameliorated cardiac function and regenerated new cardiac cells. However, human patients needing cardiac reparative therapies generally possess an array of cardiovascular risk factors such as hypercholesterolemia (HC), diabetes, hypertension etc. With the recent surge of interest in cell therapies for patients, it is important to understand the impact of these risk factors on cell-mediated cardiac repair. In particular, HC is a highly prevalent risk factor and contributes to a range of pathophysiological consequences. Hence, the overall goal of this proposal is to investigate the impact of HC on CSC-mediated cardiac repair. Our fundamental hypothesis is that depending on the specific conditions, cholesterol can be beneficial or detrimental in CSC-mediated cardiac repair. We propose that mild elevations of plasma cholesterol or the presence of the minimally oxidatively modified form of LDL-cholesterol precondition both the myocardium and the CSCs; the resulting combination of a primed myocardial microenvironment for cell engraftment and enhanced paracrine signaling mechanisms of preconditioned CSCs work in concert to enhance CSC-mediated cardiac repair. We further propose that marked elevations of plasma cholesterol or the presence of the completely oxidized form of LDL- cholesterol provoke oxidative injury to both the CSCs and the myocardium, leading to loss of efficacy of cell therapies for cardiac repair. We will test these hypotheses under 3 specific aims using both in vitro cultured CSCs and cardiomyocytes in the presence of differently modified LDLs and in vivo rat models of MI with different levels of plasma cholesterol. Aim 1 will determine the effects of HC on CSC-mediated cardiac repair in vivo; Aim 2 will determine the effects of LDLs on CSC function and reparative capability in vitro; and Aim 3 will determine whether pretreatment of CSCs with differently modified LDLs in vitro alters the efficacy of cardiac reparative therapy in vivo. Given that plasma cholesterol is a modifiable risk factor, but is also essential for cellular function, understanding the effects of this prevalent risk factor on stem cell-based therapies will have translational and mechanistic importance. This project will provide novel insights into a much-needed preclinical framework to develop cell-based therapies for cardiac repair in patients with cardiovascular risk factors. PUBLIC HEALTH RELEVANCE: Increasing evidence has demonstrated that adult stem/progenitor cells can repair myocardium with functional benefits in animal models of myocardial infarction and heart failure. Small clinical trials of stem cell therapy in human patients with myocardial infarction and ischemic cardiomyopathy have recapitulated these beneficial effects. Recent discovery that heart itself contains cardiac stem cells (CSCs) has sparked intense hope for the development of most promising stem cell therapies for cardiac repair because CSCs are inherently programmed to reconstitute cardiac tissue. However, in the clinical arena patients who need cardiac reparative therapies are mostly associated with cardiovascular risk factors such hypercholesterolemia, diabetes, hypertension etc. With the recent surge of interest in cell therapies for patients, it is important to understand the impacts of these risk factors on stem cell-mediated cardiac repair. Hypercholesterolemia is a most prevalent risk factor and imposes various pathophysiological impacts in the biological system. In this application, we will conduct experiements to investigate the impacts of hypercholesterolemia on CSC-mediated cardiac repaie. We will use both normocholesterolemic and hypercholesterolemic rat models of myocardial infarction. Rats with myocardial infarction will receive CSC therapy. The efficacy of CSC therapy for cardiac repair will be assessed using comprehensive evaluation of myocardial performance including echocardiography and hemodynamic pressure-volume catheterization and tissue structure repair including morphology, immunohistochemistry, light and confocal microscopy. Regardless our results are "positive" or "negative", this project will provide novel insights into preclinical framework to develop effective cell-based therapies for cardiac repair in patients with cardiovascular risk factors. Given that plasma cholesterol is a modifiable risk factor and essential for cellular function, understanding the effects of this prevalent risk factor on stem cell- based cardiac repair will have translational and mechanistic importance.

描述（由申请人提供）：越来越多的机制和转化研究支持使用基于细胞的治疗来修复因梗死而破坏的心肌组织并恢复心脏功能。成体原始细胞群的几个表型不同的亚群已被证明可以改善心肌梗死（MI）和心力衰竭动物模型的心脏结构和功能。干细胞治疗的小型临床试验已经概括了缺血性心肌病患者的这些有益效果。心脏干细胞（CSCs）的最新发现引发了对开发用于心脏修复/再生的有前景的干细胞疗法的强烈希望，因为CSCs固有地被编程以重建心脏组织。在最近的研究中，我们发现冠状动脉内输送CSCs给急性或慢性MI大鼠和慢性MI猪改善心脏功能和再生新的心脏细胞。然而，需要心脏修复治疗的人类患者通常具有一系列心血管风险因素，如高胆固醇血症（HC），糖尿病，高血压等。随着最近对患者细胞疗法的兴趣激增，了解这些风险因素对细胞介导的心脏修复的影响非常重要。特别是，HC是一种非常普遍的风险因素，并导致一系列病理生理学后果。因此，本提案的总体目标是研究HC对CSC介导的心脏修复的影响。我们的基本假设是，根据具体情况，胆固醇在CSC介导的心脏修复中可能是有益的或有害的。我们提出，血浆胆固醇的轻度升高或LDL-胆固醇的最低限度氧化修饰形式的存在预处理心肌和CSC;预处理CSC的细胞植入和增强的旁分泌信号传导机制的预处理心肌微环境的组合协同工作，以增强CSC介导的心脏修复。我们进一步提出，血浆胆固醇的显著升高或LDL-胆固醇的完全氧化形式的存在引起对CSC和心肌的氧化损伤，导致用于心脏修复的细胞疗法的功效丧失。我们将在3个特定目标下使用存在不同修饰的LDL的体外培养的CSC和心肌细胞以及具有不同血浆胆固醇水平的MI的体内大鼠模型来测试这些假设。目的1将确定HC对CSC介导的体内心脏修复的影响;目的2将确定LDL对CSC功能和体外修复能力的影响;目的3将确定体外用不同修饰的LDL预处理CSC是否会改变体内心脏修复治疗的疗效。鉴于血浆胆固醇是一种可改变的风险因素，但也是细胞功能所必需的，了解这种普遍的风险因素对基于干细胞的治疗的影响将具有翻译和机制的重要性。该项目将为急需的临床前框架提供新的见解，以开发用于心血管风险因素患者心脏修复的细胞疗法。公共卫生相关性：越来越多的证据表明成体干/祖细胞在心肌梗死和心力衰竭动物模型中具有修复心肌的功能。在心肌梗死和缺血性心肌病患者中进行的干细胞治疗的小型临床试验已经概括了这些有益的效果。最近发现心脏本身含有心脏干细胞（CSCs），这引发了人们对开发最有前途的心脏修复干细胞疗法的强烈希望，因为CSCs本身就具有重建心脏组织的功能。然而，在临床竞技场中，需要心脏修复治疗的患者大多与心血管危险因素相关，如高胆固醇血症、糖尿病、高血压等。随着最近对患者细胞治疗的兴趣激增，了解这些危险因素对干细胞介导的心脏修复的影响非常重要。高胆固醇血症是最普遍的风险因素，并在生物系统中施加各种病理生理学影响。在本申请中，我们将进行实验以研究高胆固醇血症对CSC介导的心脏修复的影响。我们将使用正常胆固醇血症和高胆固醇血症大鼠心肌梗死模型。患有心肌梗死的大鼠将接受CSC治疗。将使用心肌性能的综合评价（包括超声心动图和血流动力学压力-容积导管插入术）和组织结构修复（包括形态学、免疫组织化学、光学和共聚焦显微镜）评估CSC治疗心脏修复的疗效。无论我们的结果是“阳性”还是“阴性”，该项目都将为临床前框架提供新的见解，以开发有效的基于细胞的治疗方法，用于心血管危险因素患者的心脏修复。鉴于血浆胆固醇是一种可改变的风险因素，并且对细胞功能至关重要，因此了解这种普遍的风险因素对基于干细胞的心脏修复的影响将具有翻译和机制上的重要性。