Diabetic stroke cardiac dysfunction; treatment with CD133+Exosomes

糖尿病中风心功能不全；

• 批准号: 10242634
• 负责人: MICHAEL CHOPP
• 金额: $ 46.16万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242634
• 关键词: Address; Affect; Age; Animals; Antidiabetic Drugs; Biological; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Communication; Cells; Cerebrum; Clinical; Cognitive; Cognitive deficits; Complex; Data; Diabetes Mellitus; Dilatation - action; Dipeptidyl Peptidases; Dose; Event; Exhibits; Extracellular Space; Female; Genes; Harvest; Heart; Human; Hypertrophy; Impaired cognition; In Vitro; Investigation; Ischemic Stroke; Left Ventricular Ejection Fraction; Measures; Mediating; Messenger RNA; Metformin; MicroRNAs; Microvascular Dysfunction; Morbidity - disease rate; Mus; Myocardial; Myocardial dysfunction; Nervous System Physiology; Neurologic; Neurologic Deficit; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acids; Outcome; Pathway interactions; Patients; Play; Population; Proteins; RNA Sequences; Regulation; Role; Serum; Signal Pathway; Stroke; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Umbilical Cord Blood; Untranslated RNA; aged; base; cardioprotection; cardiovascular risk factor; clinically relevant; coronary fibrosis; design; diabetic; exosome; heart cell; heart function; improved; in vivo; indexing; knock-down; macrovascular disease; male; mortality; nano-exosomes; nanovesicle; nervous system disorder; neurorestoration; novel; novel therapeutic intervention; novel therapeutics; overexpression; post stroke; protective effect; response; sex; stroke outcome; stroke therapy; therapeutic evaluation; therapeutic target; young adult

Cardiovascular complications are primarily responsible for the high morbidity and mortality in people with stroke and diabetes mellitus (DM). Cardiovascular diseases are roughly three times higher in patients with neurological deficits than in patients without neurological diseases. DM is a prominent risk factor for cardiovascular diseases and cerebral ischemic stroke. Our preliminary data show that ischemic stroke and type two DM (T2DM) each induces cardiac dysfunction, while T2DM animals subjected to ischemic stroke exhibit profound cardiac dysfunction compared to non-stroke T2DM mice or non-T2DM stroke mice. Therefore, there is a compelling need to develop therapeutic approaches specifically designed not only to reduce neurological deficits, but also to decrease cardiac dysfunction after stroke with diabetes. Our preliminary data indicate that treatment of stroke in T2DM mice with exosomes derived from human umbilical cord blood isolated CD133+/KDR+ cells (CD133+Exo) 3 days after stroke not only improves neurological and cognitive outcome, but also significantly improves cardiac function and increases heart microRNA (miR)126 and miR29b expression. In a novel and clinically relevant approach, based on our robust preliminary data, we propose to investigate the underlying cardioprotective therapeutic mechanisms of CD133+Exo treatment of stroke in T2DM mice, and we will test the hypothesis that miR126 and miR29b mediate CD133+Exo-induced cardiac protective effects in male and female mice in vitro and in vivo. Two Aims are proposed. Aim 1: To investigate the effect of cerebral ischemic stroke and stroke-related factors (age, sex and T2DM) on cardiac and neurological function in mice. To test the therapeutic effects of CD133+Exo treatment of T2DM-stroke in male, female and aged mice, time window, dose response, multiple doses and combination with anti-diabetic drug (Metformin) studies will be performed. Aim 2: To investigate the mechanism of CD133+Exo induced cardiac protective effects in male and female T2DM-stroke mice in vitro and in vivo. We will focus on miR126 and miR29b, and will test: 1) whether CD133+Exo treatment of T2DM-stroke increases heart and serum miR126 or miR29b levels; 2) whether increasing miR126 or/and miR29b expression in heart or/and serum mediates the CD133+Exo induced cardiac beneficial effects in male and female T2DM-stroke mice; 3) whether the miR126/Spred-1 and/or the miR29b/DPP4 signaling pathways mediate CD133+Exo treatment induced myocardiocyte protection of cultured cardiomyocytes. A major significance of our investigations is that it opens up important and novel ways to understand how exogenously administered CD133+Exo communicate with and alter heart cells by means of miR delivery to thereby activate endogenous cardiac protective events. This proposal is highly clinically relevant and if successful, it will significantly impact the treatment of stroke, diabetes, and cardiac dysfunction. Importantly, this proposal will elucidate novel mechanisms of action and generate therapeutic targets for CD133+Exo treatment of cardiac dysfunction after stroke with T2DM in male, female and aged mice.

心血管并发症是高发病率和死亡率的主要原因， 中风和糖尿病（DM）。心血管疾病的发病率大约是 神经功能缺损的患者比没有神经系统疾病的患者。糖尿病是一个突出的危险因素， 心血管疾病和脑缺血性中风。我们的初步数据显示缺血性中风和 2型糖尿病（T2 DM）各诱导心功能不全，而T2 DM动物发生缺血性卒中 与非中风T2 DM小鼠或非T2 DM中风小鼠相比，表现出严重的心脏功能障碍。因此，我们认为， 迫切需要开发专门设计的治疗方法， 神经功能缺损，而且还可以减少糖尿病中风后的心功能障碍。我们的初步数据 表明用来源于人脐带血外来体治疗T2 DM小鼠的中风 卒中后3天分离的CD 133 +/KDR+细胞（CD 133 +Exo）不仅改善了神经和认知功能， 结果，但也显着改善心脏功能，并增加心脏microRNA（miR）126和miR 29 b 表情在一种新的临床相关方法中，基于我们强大的初步数据，我们建议 研究CD 133 +Exo治疗T2 DM卒中的潜在心脏保护治疗机制 我们将检验miR 126和miR 29 b介导CD 133 + Exo诱导的心脏保护性作用的假设。 体外和体内对雄性和雌性小鼠的影响。提出了两个目标。目的1：研究 缺血性脑卒中及卒中相关因素（年龄、性别和T2 DM）对心脏和神经功能的影响 对小鼠为了在雄性、雌性和老年小鼠中测试CD 133 +Exo治疗T2 DM-中风的治疗效果， 时间窗、剂量反应、多次给药和与抗糖尿病药物（美托洛尔）联合给药研究将 执行。目的2：探讨CD 133 +Exo对雄性大鼠心脏的保护作用及其机制。 雌性T2 DM-中风小鼠的体外和体内研究。我们将重点关注miR 126和miR 29 b，并将测试：1）是否 T2 DM-中风的CD 133 +Exo治疗增加心脏和血清miR 126或miR 29 b水平; 2）是否 增加心脏或/和血清中的miR 126或/和miR 29 b表达介导了CD 133 +Exo诱导的心脏炎症反应。 在雄性和雌性T2 DM-中风小鼠中的有益作用; 3）无论miR 126/Spred-1和/或miR-126/Spred-1的表达是否与T2 DM-中风小鼠的表达相关， miR 29 b/DPP 4信号通路介导CD 133 +Exo处理诱导的心肌细胞保护作用 心肌细胞我们的调查的一个重要意义是，它开辟了重要和新颖的方法， 了解外源性给予的CD 133 +Exo如何通过miR与心脏细胞通讯并改变心脏细胞 递送，从而激活内源性心脏保护事件。这一建议与临床高度相关 如果成功的话，它将对中风、糖尿病和心脏功能障碍的治疗产生重大影响。 重要的是，这项提议将阐明新的作用机制，并产生治疗靶点， CD 133 +Exo治疗雄性、雌性和老年小鼠中风后T2 DM心功能不全。

项目成果

CD133+Exosome Treatment Improves Cardiac Function after Stroke in Type 2 Diabetic Mice.

• DOI: 10.1007/s12975-020-00807-y
• 发表时间: 2021-03
• 期刊: Translational stroke research
• 影响因子: 6.9
• 作者: Venkat P;Cui C;Chen Z;Chopp M;Zacharek A;Landschoot-Ward J;Culmone L;Yang XP;Xu J;Chen J
• 通讯作者: Chen J