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（由申请方提供）：高血压可引起心血管并发症，并导致发病率和死亡率增加。蛋白激酶C、多元醇和晚期糖基化终产物（AGE）途径被认为是高血糖诱导的血管功能障碍的原因（即，内皮依赖性舒张的丧失）和心肌病（即，左心室功能障碍、肥大和心脏纤维化）。这三种途径的一个共同特点是产生活性氧，我们发现这是负责甘露糖结合凝集素（MBL）配体表达缺血/再灌注（I/R）模型。我们最近描述了急性高血糖小鼠心肌I/R后的心脏损伤加重。此外，野生型（WT）小鼠的急性高血糖症导致心脏祖细胞的损失和左心室肥大的发展。在这种急性高血糖模型中，高血糖诱导的心脏异常在MBL缺失小鼠中完全逆转。在本研究中，我们证明了MBL复合物或补体抑制的缺乏消除了急性高血糖后心脏纤维蛋白生成、血管功能障碍和炎症中的几个关键因素。该基金将描述每种补体途径（经典、替代、凝集素和终末）在急性高血糖诱导的血管病变和心肌病中的作用。我们还将描述MBL复合物和补体参与肾素-血管紧张素系统（RAS）激活和心脏自噬的特征。虽然心脏自噬可以是适应性的或适应不良的，但对高血糖症中的心脏自噬知之甚少，也没有研究过与补体的相互作用。我们提出补体激活导致心脏自噬，并代表促纤维化介质产生的集中联系，包括TGF-β，TGF-21和半乳糖凝集素-3。这项建议将继续我们的实验室的一般重点补体系统和心肌功能的分子机制，使个人在急性高血糖血管病变和心肌病的易感性进行调查。此外，这些特定的目标可能随后导致改善的风险分层，资源利用，和新的抗补体治疗的发展，以防止高血糖心血管并发症。