Vasomotor Dysfunction of Retinal Arterioles in Diabetes

糖尿病视网膜小动脉血管舒缩功能障碍

基本信息

批准号：
9020236
负责人：
TRAVIS W HEIN
金额：
$ 37.81万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9020236
关键词：
Acute Address Adult American Animal Model Antioxidants Biological Availability Blindness Blood Blood Glucose Blood Vessels Blood flow Cardiac health Cardiomyopathies Clinical Complications of Diabetes Mellitus Coronary Data Development Diabetes Mellitus Diabetic Retinopathy Endothelium Enzymes Evaluation Event Eye Eye diseases Family suidae Functional disorder Future Goals Health Heart Heart failure Heterogeneity Hour Human Hyperglycemia Insulin-Dependent Diabetes Mellitus Link MAPK14 gene MAPK8 gene MAPK9 gene Mediating Microcirculation Modeling Molecular Molecular Target Muscle function N-terminal NAD+ kinase Nitric Oxide Nutrient Nutritional Organ Outcome Oxidases Oxidative Stress Oxygen Pathology Peptide Signal Sequences Phosphorylation Phosphotransferases Production Protein Isoforms Proteins ROCK1 gene Regulation Resistance Retina Retinal Retinal Diseases Rho-associated kinase Role Signal Pathway Signal Transduction Site Smooth Muscle Staging Streptozocin Superoxides Testing Vasodilator Agents Vasomotor Vision Visual impairment Xanthine Oxidase animal model development arginase arteriole constriction diabetes control diabetic cardiomyopathy early onset endothelial dysfunction insight multicatalytic endopeptidase complex non-invasive imaging novel novel therapeutics prevent retinal damage

项目摘要

DESCRIPTION (provided by applicant): Retinopathy is a major complication of diabetes mellitus and a leading cause of blindness in American adults. Hyperglycemia is associated with reduced retinal blood flow in early diabetes, suggesting that dysfunction of arterioles may contribute to retinal damage. Interestingly, noninvasive imaging of retinal blood flow is being regarded as providing a "window" into the health of the heart. Although diabetes can impair coronary blood flow and promote cardiomyopathy, it is possible that underlying mechanisms, which remain unclear, contributing to coronary and retinal arteriolar dysfunction are different. Also, development of a diabetes animal model relevant to human microcirculation for mechanistic study of vasomotor dysfunction of arterioles from the retina and heart is lacking. To address these clinically important issues, we developed streptozocin-induced type 1 diabetes in the pig, an animal model that we have shown resembles human in retinal vasomotor regulation/dysregulation. Our preliminary data show that within 2 wk of diabetes, endothelium-dependent nitric oxide (NO)-mediated dilation of retinal and coronary arterioles is specifically impaired. Endothelial dysfunction correlates with oxidative stress and enhanced Rho kinase (ROCK) expression, and can be prevented and restored in coronary arterioles but only prevented in retinal arterioles by antioxidants and arginase blockade. It appears that signaling events leading to their vasomotor dysfunction in short-term diabetes are different. Mechanistic differences in vasodilator dysfunction under acute (3 hr) vs. prolonged (2 to 12 wk) hyperglycemia suggest that temporal control of arginase II and SIRT1, two regulatory enzymes for NO bioavailability, may mediate this pathophysiology in retinal arterioles, whereas continuous activation of c-Jun N-terminal kinase (JNK) and arginase I contributes to coronary dysfunction. However, the exact role and signaling sequence for specific ROCK isoform activation linking to oxidative stress and arginase have not been defined. Herein, we will test the hypothesis that early diabetes activates endothelial ROCK-dependent JNK-interacting protein-1 (JIP1)/JNK signaling, which enhances downstream NAD(P)H oxidase and p38-dependent proteasome activities in retinal arterioles and xanthine oxidase activity in coronary arterioles. Oxidative stress leads to temporal control of arginase II and SIRT1 with subsequent reduction of NO-mediated dilation in retinal arterioles, whereas prolonged elevation of arginase I sustains coronary dysfunction. We will pursue 3 specific aims: (1) Determine whether enhanced ROCK-dependent phosphorylation of JIP1 contributes to diabetes-induced dysfunction of retinal and coronary arterioles by increasing oxidative stress. (2) Determine whether enhanced JNK-dependent oxidase signaling contributes to diabetes-induced dysfunction of retinal and coronary arterioles. (3) Determine whether enhanced arginase activity and p38-induced activation of proteasomes contribute to temporal control of diabetes-induced dysfunction of retinal and coronary arterioles. Outcomes will identify novel targets involved in retinal and coronary arteriolar dysfunction during early diabetes.

描述（由申请人提供）：视网膜病是糖尿病的主要并发症，也是美国成年人失明的主要原因。高血糖与早期糖尿病的视网膜血流减少有关，这表明小动脉功能障碍可能导致视网膜损伤。有趣的是，视网膜血流的无创成像被认为为心脏健康提供了“窗口”。尽管糖尿病会损害冠状动脉血流并促进心肌病，但尚不清楚的基本机制可能导致冠状动脉和视网膜动脉功能障碍有所不同。同样，缺乏与人类微循环相关的糖尿病动物模型的发展，以研究视网膜和心脏的动脉功能障碍的机械研究。为了解决这些临床上重要的问题，我们在猪中开发了链霉菌蛋白诱导的1型糖尿病，这是一种动物模型，我们显示出类似于视网膜血管舒缩调节/失调的人。我们的初步数据表明，在2周的糖尿病中，内皮依赖性一氧化氮（NO）介导的视网膜和冠状动脉的扩张受到特异性损害。内皮功能障碍与氧化应激和增强的Rho激酶（岩石）表达相关，并且可以在冠状动脉中预防和恢复，但仅在视网膜动脉中被抗氧化剂和精氨酸酶阻滞剂预防。看来短期糖尿病中导致血管舒缩功能障碍的信号传导事件不同。在急性（3小时）下与长时间（2至12周）高血糖的血管舒张功能障碍的机理差异表明，精氨酸酶II和SIRT1的时间控制，两种调节酶，无生物利用性，可以介导这种病理学，并在视网膜上进行了这种病理学，以及c-n tental n n tental intental n tental of tenter n tenter of tenter（jjun n tental of tenter of tenter of con-tenter of（jjun）（jJun）（jJun n tenter of con-jjun of（jjun）导致冠状动脉功能障碍。但是，尚未定义与氧化应激和精氨酸酶相关的特定岩石同工型激活的确切作用和信号传导序列。在此，我们将测试假设早期糖尿病会激活内皮岩石依赖性的JNK相互作用蛋白-1（JIP1）/JNK信号，从而增强了视网膜动脉和异氨酸氧化酶活性的视网膜动脉中的NAD NAD NAD NAD（P）H氧化酶和p38依赖性蛋白酶体活性。氧化应激会导致精氨酸酶II和SIRT1的时间控制，随后减少视网膜动脉中无介导的扩张，而精氨酸酶I的延长升高会持续冠状动脉功能障碍。我们将追求3个具体目标：（1）确定JIP1的岩石依赖性磷酸化是否会导致糖尿病诱导的视网膜和冠状动脉功能障碍通过增加氧化应激。（2）确定增强的JNK依赖性氧化酶信号是否有助于糖尿病诱导的视网膜和冠状动脉动脉功能障碍。（3）确定是否增强的精氨酸酶活性和p38诱导的蛋白酶体激活是否有助于糖尿病诱导的视网膜和冠状动脉功能障碍的时间控制。结局将确定糖尿病早期视网膜和冠状动脉功能障碍涉及的新靶标。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Newly Identified Peptide, Peptide Lv, Promotes Pathological Angiogenesis.

新鉴定的肽 Lv 可促进病理性血管生成。

DOI：
10.1161/jaha.119.013673
发表时间：
2019
期刊：
Journal of the American Heart Association
影响因子：
5.4
作者：
Shi,Liheng;Zhao,Min;Abbey,ColetteA;Tsai,Shu-Huai;Xie,Wankun;Pham,Dylan;Chapman,Samantha;Bayless,KaylaJ;Hein,TravisW;RosaJr,RobertH;Ko,MichaelL;Kuo,Lih;Ko,GladysY-P
通讯作者：
Ko,GladysY-P

Constriction of Retinal Venules to Endothelin-1: Obligatory Roles of ETA Receptors, Extracellular Calcium Entry, and Rho Kinase.