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.

心血管并发症是导致患者高发病率和死亡率的主要原因 中风和糖尿病（DM）。患有以下疾病的患者患心血管疾病的几率大约是其三倍 神经功能缺损的程度高于无神经系统疾病的患者。 DM 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 二型糖尿病（T2DM）均会诱发心脏功能障碍，而 T2DM 动物会发生缺血性中风 与非中风 T2DM 小鼠或非 T2DM 中风小鼠相比，表现出严重的心脏功能障碍。所以， 迫切需要开发专门设计的治疗方法，不仅可以减少 神经功能缺陷，还可以减少糖尿病中风后的心脏功能障碍。我们的初步数据 表明使用源自人脐带血的外泌体治疗 T2DM 小鼠中风 中风后 3 天分离的 CD133+/KDR+ 细胞 (CD133+Exo) 不仅可以改善神经系统和认知功能 结果，而且还显着改善心脏功能并增加心脏 microRNA (miR)126 和 miR29b 表达。基于我们可靠的初步数据，我们建议采用一种新颖且与临床相关的方法 探讨 CD133+Exo 治疗 T2DM 中风的潜在心脏保护治疗机制 小鼠，我们将测试 miR126 和 miR29b 介导 CD133+Exo 诱导的心脏保护作用的假设 对雄性和雌性小鼠体外和体内的影响。提出了两个目标。目标 1：研究效果 脑缺血性卒中和卒中相关因素（年龄、性别和 T2DM）对心脏和神经功能的影响 在小鼠中。为了测试 CD133+Exo 治疗雄性、雌性和老年小鼠 T2DM 中风的治疗效果， 时间窗、剂量反应、多次剂量以及与抗糖尿病药物（二甲双胍）联合研究将 执行。目的2：探讨CD133+Exo对男性和女性心脏保护作用的机制 雌性 T2DM 中风小鼠的体外和体内实验。我们将重点关注 miR126 和 miR29b，并将测试：1）是否 CD133+Exo 治疗 T2DM 中风可增加心脏和血清 miR126 或 miR29b 水平； 2）是否 增加心脏或/和血清中的 miR126 或/和 miR29b 表达介导 CD133+Exo 诱导的心脏 对雄性和雌性 T2DM 中风小鼠的有益作用； 3) 是否是 miR126/Spred-1 和/或 miR29b/DPP4信号通路介导CD133+Exo处理诱导培养的心肌细胞保护 心肌细胞。我们研究的一个重要意义在于，它开辟了重要而新颖的方法 了解外源性给予的 CD133+Exo 如何通过 miR 与心脏细胞通信并改变心脏细胞 递送从而激活内源性心脏保护事件。该建议具有高度的临床相关性 如果成功，它将显着影响中风、糖尿病和心脏功能障碍的治疗。 重要的是，该提案将阐明新的作用机制并产生治疗靶点 CD133+Exo 治疗雄性、雌性和老年小鼠中风后 T2DM 心功能障碍。

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