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）：安装机械和翻译研究支持使用基于细胞的疗法来修复因梗塞破坏并恢复心脏功能而破坏的心肌组织。已经证明，几种表型不同的原始细胞群体的表型不同的子集可改善心肌梗塞（MI）和心力衰竭的动物模型中的心脏结构和功能。干细胞疗法的小型临床试验对缺血性心肌病患者概括了这些有益作用。最近发现的心脏干细胞（CSC）为开发有希望的干细胞疗法以进行心脏修复/再生带来了强烈的希望，因为CSC固有地编程以重建心脏组织。在最近的研究中，我们发现CSC在急性或慢性MI的大鼠以及具有慢性MI减轻心脏功能并再生新心脏细胞的猪上递送。但是，需要心脏修复疗法的人类患者通常具有一系列心血管危险因素，例如高胆固醇血症（HC），糖尿病，高血压等，随着最近对患者细胞疗法的兴趣激增，重要的是了解这些危险因素对细胞介导的心脏修复的影响很重要。特别是，HC是高度普遍的危险因素，并导致一系列病理生理后果。因此，该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，根据特定条件，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氧化氧化改性的LDL-胆固醇前提的最小化形式的存在。启动的心肌微环境和增强的预处理CSC的旁分泌信号传导机制的结合起作用，以增强CSC介导的心脏修复。我们进一步提出，血浆胆固醇的升高或完全氧化的LDL-胆固醇形式的存在对CSC和心肌造成氧化损伤，从而导致细胞疗法的心脏修复功效丧失。我们将在3个特定目的下使用体外培养的CSC和心肌细胞在存在不同修饰的LDL和具有不同水平等离子体胆固醇的MI的体内大鼠模型的情况下测试这些假设。 AIM 1将确定HC对体内CSC介导的心脏修复的影响； AIM 2将确定LDLS对CSC功能和体外修复能力的影响； AIM 3将确定在体外具有不同修饰的LDL的CSC预处理是否会改变体内心脏修复治疗的功效。鉴于血浆胆固醇是可修改的危险因素，但对于细胞功能也是必不可少的，因此了解这种普遍危险因素对基于干细胞的疗法的影响将具有转化和机械的重要性。该项目将为急需的临床前框架提供新的见解，以开发患有心血管危险因素患者心脏修复的基于细胞的疗法。公共卫生相关性：越来越多的证据表明，成年的茎/祖细胞可以在心肌梗塞和心力衰竭的动物模型中修复心肌。在心肌梗塞和缺血性心肌病的人类患者中，干细胞治疗的小型临床试验已概括了这些有益作用。最近发现，心脏本身含有心脏干细胞（CSC），这对开发最有前途的干细胞疗法进行心脏修复产生了巨大的希望，因为CSC固有地编程以重建心脏组织。但是，在需要心脏修复疗法的临床竞技场患者中，主要与心血管危险因素（如高胆固醇血症，糖尿病，高血压等）有关，随着最近对患者细胞疗法的兴趣激增，重要的是了解这些危险因素对干细胞介导的心脏介导的心脏修复的影响很重要。高胆固醇血症是最普遍的危险因素，并在生物系统中施加了各种病理生理影响。在此应用中，我们将进行体验，以研究高胆固醇血症对CSC介导的心脏repaie的影响。我们将使用心肌梗塞的常胆脂脂和高胆固醇大鼠模型。具有心肌梗塞的大鼠将接受CSC疗法。 CSC治疗对心脏修复的疗效将通过对心肌性能的全面评估进行评估，包括超声心动图和血液动力学压力量导管插入术和组织结构修复，包括形态学，免疫组织化学，光和共聚焦显微镜。不管我们的结果是“正”或“负”，该项目将为临床前框架提供新的见解，以开发有效的心血管危险因素患者心脏修复的有效细胞疗法。鉴于血浆胆固醇是可修改的危险因素，对于细胞功能而言至关重要，因此了解这种普遍的危险因素对基于干细胞的心脏修复的影响将具有转化和机理的重要性。