Innate Immunity and Cardiovascular Function

先天免疫和心血管功能

• 批准号: 8586247
• 负责人: GREGORY L STAHL
• 金额: $ 56.54万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586247
• 关键词: Acute; Advanced Glycosylation End Products; Area; Attenuated; Autophagocytosis; Binding; Biological Models; Blood Glucose; Blood Vessels; Cardiac; Cardiomyopathies; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cells; Classical Complement Pathway; Complement; Complement 5a; Complement Activation; Complement Inactivators; Complement Membrane Attack Complex; Complex; Congenital Heart Defects; Data; Development; Diabetes Mellitus; Endothelium; Event; Fibrosis; Functional disorder; Galectin 3; Gap Junctions; Generations; Glucose; Grant; Health; Heart Hypertrophy; Human; Hyperglycemia; Hyperglycemic Mice; Hypertrophy; Immune; Individual; Inflammation; Inflammatory; Injury; Investigation; Ischemia; Kidney; Knockout Mice; Laboratories; Lead; Lectin; Left Ventricular Dysfunction; Left Ventricular Hypertrophy; Left Ventricular Remodeling; Ligands; Lung; Mannose Binding Lectin; Mannose-Binding Lectins; Mediating; Mediator of activation protein; Microvascular Dysfunction; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Natural Immunity; Organ; Oxidative Stress; Pathway interactions; Play; Prevention; Production; Protein Kinase C; Reactive Oxygen Species; Regulation; Relaxation; Renin-Angiotensin System; Reperfusion Therapy; Reporting; Resources; Risk; Risk Factors; Role; Signal Pathway; Skin; Stem cells; Stratification; Therapeutic; Tissues; Transgenic Mice; Vascular Diseases; Ventricular Remodeling; Wild Type Mouse; biological systems; complement pathway; complement system; diabetic cardiomyopathy; fibrogenesis; improved; mortality; mouse model; novel; novel strategies; polyol; pressure; receptor; receptor for advanced glycation endproducts; therapeutic target

DESCRIPTION (provided by applicant): Hyperglycemia induces cardiovascular complications associated with increased morbidity and mortality. The protein kinase C, polyol, and advanced glycation end products (AGE) pathways are thought to be responsible for hyperglycemia-induced vascular dysfunction (i.e., loss of endothelium-dependent relaxation) and cardiomyopathy (i.e., left ventricular dysfunction, hypertrophy and cardiac fibrosis). A common feature of these three pathways is the production of reactive oxygen species, which we showed to be responsible for mannose binding lectin (MBL) ligand expression in ischemia/reperfusion (I/R) models. We recently described augmented cardiac injury in acute hyperglycemic mice following myocardial I/R. Further, acute hyperglycemia in wild type (WT) mice caused a loss of cardiac progenitor cells and the development of left ventricular hypertrophy. Hyperglycemia-induced cardiac abnormalities in this acute hyperglycemia model were completely reversed in MBL null mice. In the present grant, we demonstrate that the absence of the MBL complex or complement inhibition eliminates several key factors involved in the cardiac fibrinogenesis, vascular dysfunction, and inflammation following acute hyperglycemia. This grant will characterize the role of each complement pathway (classical, alternative, lectin and terminal) in the vasculopathy and cardiomyopathy induced by acute hyperglycemia. We will also characterize the involvement of the MBL complex and complement in renin-angiotensin system (RAS) activation and cardiac autophagy. While cardiac autophagy can be adaptive or maladaptive, little is known about cardiac autophagy in hyperglycemia and no interactions with complement have been investigated. We propose that complement activation leads to cardiac autophagy and represents a centralized nexus for pro-fibrotic mediator production including RAGE, TGF-21 and galectin- 3. This proposal will continue our laboratory's general focus on the complement system and myocardial function by investigating the molecular mechanisms that predispose individuals to vasculopathy and cardiomyopathy during acute hyperglycemia. Furthermore, these specific aims may subsequently lead to improved risk stratification, resource utilization, and the development of novel anti-complement therapies to protect against hyperglycemic cardiovascular complications.

描述（由申请人提供）：高血糖引起心血管并发症，增加发病率和死亡率。蛋白激酶C、多元醇和晚期糖基化终产物（AGE）通路被认为是高血糖诱导的血管功能障碍（即内皮依赖性松弛丧失）和心肌病（即左心室功能障碍、肥厚和心脏纤维化）的原因。这三种途径的共同特征是产生活性氧，我们发现活性氧在缺血/再灌注（I/R）模型中负责甘露糖结合凝集素（MBL）配体的表达。我们最近描述了急性高血糖小鼠心肌I/R后心脏损伤的增强。此外，野生型（WT）小鼠的急性高血糖导致心脏祖细胞的丢失和左心室肥厚的发展。在MBL缺失小鼠中，急性高血糖模型中高血糖引起的心脏异常完全逆转。在目前的研究中，我们证明了MBL复合物的缺失或补体抑制消除了几个涉及心脏纤维蛋白生成、血管功能障碍和急性高血糖后炎症的关键因素。该资助将描述每种补体途径（经典、替代、凝集素和终末）在急性高血糖引起的血管病变和心肌病中的作用。我们还将描述MBL复合物和补体在肾素-血管紧张素系统（RAS）激活和心脏自噬中的作用。虽然心脏自噬可以是适应性的或不适应性的，但对高血糖时的心脏自噬知之甚少，也没有研究其与补体的相互作用。我们认为补体激活导致心脏自噬，并代表了促纤维化介质生产的集中联系，包括RAGE， TGF-21和凝集素- 3。本研究将继续我们实验室对补体系统和心肌功能的总体关注，研究急性高血糖患者易患血管病变和心肌病的分子机制。此外，这些特定目标可能随后导致改善风险分层、资源利用和开发新的抗补体疗法，以防止高血糖心血管并发症。