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.

心血管并发症是高血压患者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以下患者的三倍 神经功能缺陷的患者比没有神经疾病的患者更少。糖尿病是患糖尿病的显著危险因素 心血管疾病和脑缺血中风。我们的初步数据显示，缺血性中风和 2型糖尿病(T2 DM)均可导致心功能障碍，而T2 DM动物发生缺血性卒中 与非卒中T2 DM小鼠或非T2 DM卒中小鼠相比，表现出严重的心功能障碍。因此， 迫切需要开发专门设计的治疗方法，不仅是为了减少 不仅可以减少糖尿病患者中风后的心功能障碍，还可以改善神经功能障碍。我们的初步数据 人脐血外切体治疗2型糖尿病小鼠卒中 卒中后3天分离的CD133+/KDR+细胞(CD133+Exo)不仅改善神经和认知功能 结果，但也显著改善心功能和增加心脏microRNA(MiR)126和miR29b 表情。在一种新的和临床相关的方法中，基于我们强大的初步数据，我们建议 CD133+Exo治疗2型糖尿病卒中的心肌保护作用机制探讨 小鼠，我们将检验miR126和miR29b介导CD133+Exo诱导的心脏保护的假设 在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：探讨三七总皂甙的作用。 脑缺血性卒中及卒中相关因素(年龄、性别、2型糖尿病)对心脏和神经功能的影响 在老鼠身上。目的：观察CD133+Exo对雄性、雌性和老年小鼠T2 DM卒中的治疗作用。 将进行时间窗口、剂量反应、多剂量和与抗糖尿病药物(二甲双胍)的联合研究 已执行。目的：探讨CD133+Exo对雄性和大鼠心脏保护作用的机制。 雌性T2 DM卒中小鼠的体内外实验。我们将重点关注miR126和miR29b，并将测试：1)是否 CD133+Exo治疗T2 DM卒中可提高心脏和血清miR126或miR29b水平；2) 心脏或/和血清中miR126或/和miR29b表达增加介导CD133+Exo诱导的心脏 对雄性和雌性T2 DM卒中小鼠的有益影响；3)miR126/Spred-1和/或 MiR29b/DPP4信号通路介导CD133+Exo对培养心肌细胞的保护作用 心肌细胞。我们的调查的一个主要意义是它开辟了重要的和新颖的方法来 了解外源性CD133+Exo如何通过miR与心肌细胞沟通和改变 递送从而激活内源性心脏保护事件。这项建议具有高度的临床相关性。 如果成功，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，并产生治疗目标 CD133+Exo治疗2型糖尿病卒中后心功能不全的实验研究

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