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。常规 治疗DCM的疗法包括血糖控制、高血压管理、降脂和 生活方式管理。然而，没有可用的治疗策略专门针对 DCM的发病机制。需要对扩张型心肌病的发病机制有更深入的了解， 改善治疗策略。 基质细胞衍生因子-1（SDF-1）属于C-X-C基序趋化因子家族。它控制多种细胞 通过与其受体CXCR 4和CXCR 7相互作用发挥作用。心肌SDF-1瞬时上调 在缺血期间或梗塞后，可以吸引干细胞到损伤部位， 再生和血管生成。外源性SDF-1可以帮助预防心肌梗死， 缺血/再灌注损伤通过干细胞依赖性和非依赖性机制。然而，作用 SDF-1-CXCR 4/CXCR 7系统在DCM中的作用机制尚不明确。 越来越多的证据表明，糖尿病诱导的生长因子如SDF-1的缺乏是糖尿病的一个重要原因。 与糖尿病心血管并发症有关。在一项初步研究中，PI显示， SDF-1的表达在患有1型和2型糖尿病的小鼠的心脏组织中显著下调， 而受体表达水平不受影响。PI认为缺乏心脏SDF-1可能 补充SDF-1可直接保护心肌细胞。作为初步测试 将培养的心肌细胞暴露于经SDF-1预处理的棕榈酸酯模拟的糖尿病脂毒性。 这些研究表明，SDF-1通过CXCR 7-保护棕榈酸酯诱导的细胞死亡，但不能通过CXCR 7-诱导细胞死亡。 CXCR 4-介导的AMP活化蛋白激酶（AMPK）活化。研究结果具有重要意义 因为他们证明SDF-1可以提供直接保护，不依赖于糖尿病心脏细胞死亡 干细胞因此，确定体内保护是否涉及相同的直接作用是至关重要的， 在分离的心肌细胞上鉴定SDF-1。基于CXCR 4和CXCR 7在 心血管疾病，假设糖尿病小鼠的SDF-1治疗直接保护了心血管疾病， CXCR 7介导AMPK激活诱导糖尿病心肌细胞死亡和心脏重塑 并且SDF-1治疗可以最终预防DCM。 这一假设将通过三个具体目标进行检验：（1）确定直接心肌细胞效应 （2）确定SDF-1信号转导是否通过CXCR 7介导 （3）确定AMPK是否介导SDF-1/CXCR 7 防止DCM。 本项目将为SDF-1-CXCR 4和/或-CXCR 7在细胞内的相互作用提供基础证据。 心肌细胞作为一个新的治疗靶点，预防扩张型心肌病在未来的临床研究。