A novel mechanism of stromal cell-derived factor 1 protection against diabetic cardiomyopathy

基质细胞衍生因子 1 预防糖尿病心肌病的新机制

基本信息

批准号：
9883646
负责人：
Yi Tan
金额：
$ 38.38万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883646
关键词：
5&apos -AMP-activated protein kinase Adhesions Apoptosis Bone Marrow CXCR4 Receptors CXCR4 gene Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Catalytic Domain Cell Death Cell physiology Cells Cessation of life Chemotaxis Chronic Cytoskeletal Modeling Data Development Diabetes Mellitus Diabetic Angiopathies Diabetic mouse Dysplasia Exposure to Family Future GTP-Binding Proteins Genes Growth Factor Heart High Fat Diet In Vitro Infarction Injections Injury Insulin-Dependent Diabetes Mellitus Interleukin-6 Ischemia Knock-out Knockout Mice Life Style Lipids MAP Kinase Gene Mediating Modeling Mus Myocardial Myocardial Infarction Myocardial Ischemia Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Palmitates Paper Pathogenesis Pathogenicity Pathologic Pathology Phosphorylation Phosphotransferases Prevention Process Production Protein Kinase Reperfusion Injury Role Signal Pathway Signal Transduction Site Streptozocin Stromal Cell-Derived Factor 1 System Testing Therapeutic Tissues Transgenes Transgenic Organisms Transplantation Ventricular septum antioxidant therapy base beta-arrestin cardiac angiogenesis cardiac regeneration chemokine clinical investigation clinical practice conditional knockout conventional therapy diabetic diabetic cardiomyopathy diabetic patient glycemic control heart damage hypertension control improved in vivo insight new therapeutic target novel p38 Mitogen Activated Protein Kinase prevent receptor receptor expression stem cells treatment strategy

项目摘要

Diabetic cardiomyopathy (DCM) is one of the major chronic complications in diabetic patients. Conventional therapies for treatment of DCM include glycemic control, management of hypertension, lowering lipid and life-style management. However, there are no treatment strategies available that specifically target the pathogenesis of DCM. Greater understanding of the pathogenic mechanism of DCM is needed to develop improved therapeutic strategies. Stromal cell-derived factor-1 (SDF-1) belongs to C-X-C motif chemokine family. It controls diverse cell functions by interacting with its receptors, CXCR4 and CXCR7. Myocardial SDF-1 is transiently up-regulated during ischemia or after infarction and can attract stem cells to the injury site contributing to cardiac regeneration and angiogenesis. Exogenous SDF-1 can help prevent myocardial infarction and ischemia/reperfusion injury through stem cell-dependent and -independent mechanisms. However, the role and mechanism of the SDF-1-CXCR4/CXCR7 system in DCM has not been established. Accumulating evidence indicates that diabetes-induced deficiency of growth factors such as SDF-1 is associated with diabetic cardiovascular complications. In a preliminary study, the PI showed that the expression of SDF-1 is notably down-regulated in the cardiac tissue of mice with type 1 and type 2 diabetes, while the receptor expression levels are unaffected. The PI considered that lack of cardiac SDF-1 may contribute to DCM and supplementary SDF-1 may provide direct cardiomyocyte protection. As an initial test cultured cardiac cells were exposed to palmitate-mimicked diabetic lipotoxicity with SDF-1 pretreatment. These studies showed that SDF-1 protected against palmitate-induced cell death via CXCR7-, but not CXCR4-, mediated AMP-activated protein kinase (AMPK) activation. The results are of great significance since they demonstrate SDF-1 can provide direct protection against diabetic cardiac cell death independent of stem cells. Therefore, it is critical to determine if in vivo protection involves the same direct actions by SDF-1 identified on isolated cardiomyocytes. Based on the critical role of CXCR4 and CXCR7 in cardiovascular diseases, it is hypothesized that SDF-1 treatment of diabetic mice directly protects against diabetes-induced cardiomyocyte death and cardiac remodeling via CXCR7-mediated activation of AMPK and that SDF-1 treatment can ultimately prevent DCM. This hypothesis will be tested through three specific aims: (1) to determine the direct cardiomyocyte effects of SDF-1 in protection against DCM; (2) to determine whether SDF-1 signaling through CXCR7 mediates protection against DCM, independently of CXCR4; (3) to determine whether AMPK mediates SDF-1/CXCR7 protection against DCM. This project will provide fundamental evidence for the interaction of SDF-1-CXCR4 and/or -CXCR7 at the cardiomyocyte as a new therapeutic target for the prevention of DCM in future clinical investigations.

糖尿病心肌病（DCM）是糖尿病患者主要的慢性并发症之一。传统的 DCM 的治疗方法包括控制血糖、控制高血压、降脂和生活方式管理。然而，目前尚无专门针对该疾病的治疗策略。 DCM 的发病机制。需要进一步了解 DCM 的致病机制改进的治疗策略。基质细胞衍生因子-1 (SDF-1) 属于 C-X-C 基序趋化因子家族。它控制着不同的细胞通过与其受体 CXCR4 和 CXCR7 相互作用发挥作用。心肌 SDF-1 短暂上调在缺血期间或梗塞后，可以将干细胞吸引到损伤部位，从而促进心脏功能再生和血管生成。外源性SDF-1有助于预防心肌梗塞和通过干细胞依赖性和非依赖性机制造成缺血/再灌注损伤。然而，角色 SDF-1-CXCR4/CXCR7系统在DCM中的作用机制尚未建立。越来越多的证据表明，糖尿病引起的生长因子（例如 SDF-1）缺乏与与糖尿病心血管并发症有关。在初步研究中，PI 表明 SDF-1 的表达在 1 型和 2 型糖尿病小鼠的心脏组织中显着下调，而受体表达水平不受影响。 PI 认为缺乏心脏 SDF-1 可能有助于 DCM，补充 SDF-1 可以提供直接的心肌细胞保护。作为初步测试培养的心肌细胞经 SDF-1 预处理后暴露于模拟棕榈酸酯的糖尿病脂毒性。这些研究表明，SDF-1 通过 CXCR7- 防止棕榈酸酯诱导的细胞死亡，但不能 CXCR4-介导 AMP 激活蛋白激酶 (AMPK) 激活。结果意义重大因为他们证明 SDF-1 可以提供直接保护，防止糖尿病心肌细胞死亡干细胞。因此，确定体内保护是否涉及相同的直接作用至关重要在分离的心肌细胞上鉴定出 SDF-1。基于 CXCR4 和 CXCR7 在心血管疾病，假设 SDF-1 治疗糖尿病小鼠可直接预防心血管疾病通过 CXCR7 介导的 AMPK 激活糖尿病引起的心肌细胞死亡和心脏重塑 SDF-1 治疗最终可以预防 DCM。该假设将通过三个具体目标进行检验：（1）确定直接的心肌细胞效应 SDF-1 预防 DCM 的作用； (2) 判断SDF-1信令是否通过CXCR7介导针对 DCM 的保护，独立于 CXCR4； (3)确定AMPK是否介导SDF-1/CXCR7 预防 DCM。该项目将为 SDF-1-CXCR4 和/或 -CXCR7 在心肌细胞作为未来临床研究中预防 DCM 的新治疗靶点。