Mechanisms of Coronary Arteriolar Dysfunction in Type 2 Diabetes

2 型糖尿病冠状动脉功能障碍的机制

基本信息

批准号：
8383472
负责人：
KHALID MATROUGUI
金额：
$ 34.52万
依托单位：
EASTERN VIRGINIA MEDICAL SCHOOL
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：
2010-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8383472
关键词：
Address Adenoviruses Caliber Cardiovascular Diseases Cessation of life Chemosensitization Complex Coronary Coronary Arteriosclerosis Data Development Diabetes Mellitus Diabetic Angiopathies Diabetic mouse Disease Endothelial Cells Epidermal Growth Factor Receptor Etiology Functional disorder Generations Goals Heart Heart Diseases In Vitro Investigation Knockout Mice Laboratories Link Measurement Mediating Molecular Biology Morbidity - disease rate Mus Myocardial Ischemia NADP NF-kappa B Non-Insulin-Dependent Diabetes Mellitus Nuclear Oxidative Stress Pathology Pathway interactions Pharmacology Phosphorylation Poly(ADP-ribose) Polymerases Prevalence Production Protein Tyrosine Kinase Receptor Gene Relaxation Research Research Personnel Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Stream Superoxides Technology Testing Vascular Diseases Vascular Endothelial Cell acetovanillone arteriole burden of illness cell growth cell motility constriction db/db mouse diabetic diabetic patient improved in vivo insight leptin receptor migration mimetics nuclear factor 1 p65 poly(ADP-ribose)polymerase-1, mouse polyethylene glycol-superoxide dismutase pressure public health relevance response therapy development

项目摘要

DESCRIPTION (provided by applicant): Coronary arteriolar function is highly dependent on the integrity of endothelial cells (EC) and vascular smooth muscle cells (VSMC). Type 2 diabetes is associated with increased prevalence of ischemic heart disease, generally related to coronary artery disease that is associated with increased morbidity and death in diabetic patients. Epidermal growth factor receptor (EGFR) tyrosine kinase, of the many factors involved in cell growth and migration has been shown to be critical in the development of microvascular myogenic tone expressed as microvascular constriction in response to pressure increases. Our studies show an exacerbation of EGFR tyrosine kinase phosphorylation in coronary arteriolar from type 2 diabetic mice (db-/db- mice lacking leptin receptor gene) associated with coronary arteriolar dysfunction characterized by a reduced endothelial-dependent relaxation and potentiation of myogenic tone. Interestingly, in vivo inhibition of EGFR tyrosine kinase in db-/db- mice significantly improves coronary arteriolar function. Thus, enhanced EGFR tyrosine kinase in diabetes could be a critical up stream signal leading to a myriad of downstream signaling including oxidative stress, NFkB and PARP-1. More importantly, oxidative stress, nuclear factor kappa Beta (NFkB-transcriptional and nuclear factor) and poly(ADP-ribose)polymerase (PARP-1 nuclear factor), which are highly implicated in the etiology and progression of type 2 diabetes, could be critical in coronary arteriolar dysfunction in diabetes. Our preliminary data indicate an increase in oxidative stress (superoxide; O2.-), p65- NFkB activity and PARP-1 activity in coronary arterioles from db-/db- mice. Despite these connections, there has been no link determined between the coronary arteriolar pathology of diabetes with EGFR tyrosine kinase, oxidative stress, NFkB and PARP-1 pathway. Therefore, our central hypothesis is that exacerbation of EGFR tyrosine kinase phosphorylation leads to the increased ROS, NFkB and PARP activity, which in turn are responsible for coronary arteriolar dysfunction in type 2 diabetes. We will determine that: Aim 1. EGFR tyrosine kinase inhibition reduces O2.-, p65-NFkB and PARP activity, and improves coronary arteriolar function in db-/db- mice; Aim 2. Inhibition of O2.- production or scavenging of O2.- in db-/db- mice improves coronary arteriolar EC and VSMC dysfunction; Aim 3. Increased p65-NFkB and PARP-1 activities are critical in coronary arteriolar dysfunction in db-/db- mice. The successful completion of this project will determine the mechanisms how exacerbation of EGFR tyrosine kinase leads to the increased oxidative stress, NFkB and PARP-1 activity, which in turn are responsible for coronary arteriolar dysfunction, and will provide new insight into the vasculopathy mechanisms in diabetes.

描述（由申请人提供）：冠状动脉功能高度取决于内皮细胞（EC）和血管平滑肌细胞（VSMC）的完整性。 2型糖尿病与缺血性心脏病的患病率增加有关，这通常与冠状动脉疾病有关，冠状动脉疾病与糖尿病患者的发病率和死亡有关。表皮生长因子受体（EGFR）酪氨酸激酶，涉及细胞生长和迁移的许多因素已被证明在微血管肌原性张力的发展中至关重要，表达为在压力增加时微血管收缩。我们的研究表明，来自2型糖尿病小鼠（缺乏瘦素受体基因的DB-/db-小鼠）的冠状动脉动脉中EGFR酪氨酸激酶磷酸化的加剧，与冠状动脉动脉功能障碍相关的冠状动脉功能障碍，其表征的表征是依赖性依赖性依赖性依赖性依赖性依赖性依赖性依赖性依赖性依赖性降低和肌张力。有趣的是，DB-/DB-小鼠中EGFR酪氨酸激酶的体内抑制可显着改善冠状动脉功能。因此，糖尿病中增强的EGFR酪氨酸激酶可能是一个关键的上流信号，导致无数的下游信号传导，包括氧化应激，NFKB和PARP-1。更重要的是，氧化应激，核因子KAPPAβ（NFKB转录和核因子和核因子）和聚（ADP-核糖）聚合酶（PARP-1核因子）高度与2型糖尿病的病因和进展有关，在糖尿病中可能至关重要。我们的初步数据表明氧化应激（超氧化物； O2.-），p65-NFKB活性和db-/db-小鼠冠状动脉动脉中的PARP-1活性。尽管有这些联系，但糖尿病的冠状动脉病理学与EGFR酪氨酸激酶，氧化应激，NFKB和PARP-1途径之间尚无联系。因此，我们的中心假设是，EGFR酪氨酸激酶磷酸化的加剧导致ROS，NFKB和PARP活性增加，这又导致2型糖尿病中的冠状动脉动脉功能障碍。我们将确定：AIM1。EGFR酪氨酸激酶抑制作用可减少O2.-，p65-NFKB和PARP活性，并改善db-/db-小鼠中冠状动脉动脉功能；目标2。抑制O2。-生产或清除O2。-在DB-/DB-小鼠中可改善冠状动脉eC和VSMC功能障碍； AIM 3。增加的P65-NFKB和PARP-1活性在DB-/DB-小鼠的冠状动脉动力障碍中至关重要。该项目的成功完成将确定EGFR酪氨酸激酶加剧如何导致氧化应激，NFKB和PARP-1活性的增加，而氧化应激，这反过来又导致了冠状动脉动脉功能障碍，并将为糖尿病患者的血管瘤机制提供新的见解。