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

• 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
• 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' -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

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）是糖尿病患者的主要慢性并发症之一。传统的 DCM治疗的疗法包括血糖控制，高血压管理，降低脂质和 生活方式管理。但是，尚无专门针对的治疗策略 DCM的发病机理。需要对DCM的致病机理有更多了解 改进的治疗策略。 基质细胞衍生的因子1（SDF-1）属于C-X-C基序趋化因子家族。它控制着各种细胞 通过与其受体CXCR4和CXCR7相互作用的功能。心肌SDF-1瞬时上调 在缺血期间或梗塞后，可以吸引干细胞进入损伤部位，导致心脏 再生和血管生成。外源SDF-1可以帮助防止心肌梗塞和 通过干细胞依赖性和非依赖性机制的缺血/再灌注损伤。但是，角色 DCM中SDF-1-CXCR4/CXCR7系统的机制尚未建立。 积累的证据表明，糖尿病引起的生长因子（例如SDF-1）的缺乏是 与糖尿病心血管并发症有关。在一项初步研究中，PI表明 SDF-1的表达在患有1型和2型糖尿病的小鼠心脏组织中明显下调， 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和补充SDF-1可以提供直接的心肌细胞保护。作为初始测试 通过SDF-1预处理，培养的心脏细胞暴露于模拟棕榈酸酯的糖尿病性脂肪毒性。 这些研究表明，SDF-1通过CXCR7-防止棕榈酸酯诱导的细胞死亡，但不是 CXCR4-介导的AMP激活蛋白激酶（AMPK）激活。结果非常重要 由于他们证明了SDF-1可以直接保护糖尿病性心脏细胞死亡独立 干细胞。因此，至关重要的是确定体内保护是否涉及相同的直接行动 SDF-1在分离的心肌细胞上鉴定。基于CXCR4和CXCR7在 心血管疾病，假设糖尿病小鼠的SDF-1治疗可直接保护 通过CXCR7介导的AMPK激活的糖尿病引起的心肌细胞死亡和心脏重塑 SDF-1治疗最终可以防止DCM。 该假设将通过三个特定目的进行检验：（1）确定直接心肌细胞效应 SDF-1在防止DCM的保护方面； （2）确定SDF-1通过CXCR7信号传导是否介导 保护DCM，独立于CXCR4； （3）确定AMPK是否介导SDF-1/CXCR7 防止DCM。 该项目将为SDF-1-CXCR4和/或-CXCR7的相互作用提供基本证据 在未来的临床研究中，心肌细胞是预防DCM的新治疗靶点。