Flow-induced coronary vasospasm in diabetic patients

糖尿病患者血流诱发的冠状血管痉挛

基本信息

批准号：
8478180
负责人：
Zsolt Bagi
金额：
$ 35.34万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8478180
关键词：
Acetylcholine Affect Age Animal Model Arachidonic Acids Arginine Arteries Blocking Antibodies Blood Platelets Blood Vessels Blood flow CD31 Antigens Caliber Cardiac Surgery procedures Cell Adhesion Molecules Cell membrane Cells Comorbidity Complication Control Groups Coronary Coronary Artery Vasospasm Coronary Vessels Coronary artery Coupled Cyclooxygenase Inhibitors Cytosolic Phospholipase A2 Data Dependence Dilatation - action Disease Distal Endothelial Cells Endothelium Ensure Enzyme Inhibitor Drugs Enzyme Inhibitors Exhibits Fluorescence Fluorescence Resonance Energy Transfer Fluorescent Dyes Fura-2 Gender Grant Heart High Prevalence Human Image Immunohistochemistry In Situ Indomethacin Inflammatory Intercellular Junctions Intervention Label Laser Scanning Confocal Microscopy Lasers Lead Lesion Life Measures Mediating Mediator of activation protein Metabolism Microcirculatory Bed Microdissection Monomeric GTP-Binding Proteins Myography Nature Nitric Oxide Nitric Oxide Synthase Non-Insulin-Dependent Diabetes Mellitus Patients Perfusion Pharmaceutical Preparations Phospholipase A2 Preventive Process Production Prostaglandins Prostaglandins I Proteins Protocols documentation Research Support Resistance Rho-associated kinase Role Sarcoplasmic Reticulum Signal Pathway Signal Transduction Spatial Distribution Surface Techniques Testing Therapeutic Therapeutic Embolization Therapeutic Intervention Thromboxane A2 Time Tissues Transfection Translating Tyrosine Phosphorylation Up-Regulation Vasodilation Vasodilator Agents Vasospasm Video Microscopy Western Blotting antibody inhibitor arginase arteriole auricular appendage cellular imaging clinical practice connexin 37 constriction cyclooxygenase 1 cyclooxygenase 2 diabetic diabetic patient feeding immunoglobulin receptor inhibitor/antagonist mouse model novel occludin percutaneous coronary intervention pressure prevent public health relevance ratiometric receptor research study response sensor spatiotemporal vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Patients with type 2 diabetes mellitus (T2-DM) have higher prevalence of no-reflow phenomenon - a poorly understood and unpredictable complication of percutaneous coronary intervention (PCI) in which diminished blood flow to distal microvascular beds persists despite the successful treatment of the occlusive lesion of the epicardial coronary artery. Current therapeutic interventions to prevent no reflow are ineffective. Preliminary observations related to this application led to my main hypothesis that small coronary arteries of diabetic patients exhibit a paradoxical constriction to sudden increases in flow, an alteration, which contributes to no reflow. I propose that RhoA-dependent co-localization of arginase I and eNOS leads to reduced NO synthesis and diminished NO-mediated dilatation in response to flow in T2-DM. I also hypothesize that stimulation of platelet endothelium cell adhesion molecule -1 (Pecam-1, known as primary flow sensor in endothelium) with increases in intraluminal flow elevates endothelial [Ca2+]i, which via inducing phospholipase A2 and arachidonic acid release leads to enhanced production of thromboxane A2 in coronary vessels of T2-DM patients. To test these hypotheses, I aim to isolate small coronary vessels from the (discarded) atrial appendages of patients with T2-DM undergoing cardiac surgery. Using small vessel pressure myography and videomicroscopy, diameter changes of the isolated, coronary arteriole (< 100 5m) exposed to sudden increase in intraluminal flow will be measured in the presence of inhibitors of specific signaling pathways. To investigate (co)localization of eNOS and arginase I as well as to detect spatial distribution and interaction of Pecam-1 laser scanning confocal microscopy and fluorescence resonance energy transfer approaches will be used in isolated, pressurized coronary arteries and coronary endothelial cells in culture. Moreover, flow-induced changes in endothelial [Ca2+]i will be measured with Fura-2 fluorescence in intact, pressurized coronary arterioles to reveal spatial differences of [Ca2+]i elevations at subcellular level. Should the results obtained in the course of the project support my hypothesis this will be the first description of Pecam-1-coupled constrictor prostanoid production in human coronary arteries. Results will also provide a novel mechanism by which spatial distribution of Pecam-1 determines the nature of vasoactive mediators released to increase in flow in T2-DM. Data obtained in this project will also help to develop novel avenues for effective therapeutic strategies, such as the use of prostanoid inhibitors at the time of PCI, to prevent no reflow in patients with T2-DM.

描述（由申请人提供）：2型糖尿病患者（T2-DM）的无流量现象的患病率较高 - 经皮冠状动脉干预（PCI）的理解不足和不可预测的并发症，尽管流血至远端的微血管层下降，但尽管成功地治疗了Eprone carterrone colderion carterion collection coctiver conterion coctiver contection likicsion。目前没有防止回流的治疗干预措施无效。与此应用有关的初步观察结果导致我的主要假设是，糖尿病患者的小冠状动脉表现出对突然增加的矛盾收缩，这种变化是一种改变，这无助于反流。我提出精氨酸酶I和eNOS的RhoA依赖性共定位会导致无合成降低，并减少了响应T2-DM流动的NO介导的扩张。我还假设血小板内皮细胞粘附分子-1（PECAM-1，被称为内皮中的原发性流动传感器）随着内膜流动的增加增加内皮[Ca2+] I，通过诱导磷脂酶A2和芳基酮酸会释放，从而增强了Thomboxane A2的产生，可增强Thomboxane A2的产生。为了检验这些假设，我的目标是将小型冠状动脉血管与接受心脏手术的T2-DM患者的（丢弃的）心房附属物分离。使用小血管压力密码和视频显微镜检查，在存在特定信号通路的抑制剂的情况下，将测量暴露于腔内流动突然增加的分离的冠状动脉动脉（<100 5m）的直径变化。为了研究（CO）（CO）eNOS和精氨酸酶I的定位，以及检测PECAM-1激光扫描共聚焦显微镜和荧光共振能量转移方法的空间分布以及相互作用，将用于培养中分离的，加压的冠状动脉和冠状动脉内皮细胞。此外，将在完整的，加压的冠状动脉动脉中以Fura-2荧光进行流动诱导的内皮[Ca2+] i的变化，以揭示[Ca2+] I高度在亚细胞水平的空间差异。如果在项目过程中获得的结果支持我的假设，那么这将是人类冠状动脉中PECAM-1偶联的束缚前列腺素产生的第一个描述。结果还将提供一种新的机制，通过该机制，PECAM-1的空间分布决定了释放的血管活性介质的性质，以增加T2-DM的流量。该项目中获得的数据还将有助于开发新的途径，以实现有效的治疗策略，例如在PCI时使用前列腺素抑制剂，以防止T2-DM患者没有回流。