Inhibition of GRK2 to Prevent Ventricular Remodeling and Heart Failure After CABG

抑制 GRK2 可预防 CABG 后心室重构和心力衰竭

基本信息

批准号：
8086228
负责人：
Shahab A Akhter
金额：
$ 39万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8086228
关键词：
Address Adenylate Cyclase Adrenergic Receptor Adult Agonist Beta-Adrenergic Receptor Kinase 1 Binding Cardiac Cardiac Myocytes Cause of Death Cells Chronic Collagen Connective Tissue Contractile Proteins Coronary Arteriosclerosis Coronary Artery Bypass Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytomegalovirus Data Deposition Depressed mood Disease Echocardiography Event Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibrosis Functional disorder G Protein-Coupled Receptor Signaling Gene Transfer Genes Goals Heart Heart failure Homeostasis Human Hypertrophy In Vitro Inferior Injection of therapeutic agent Injury Laboratories Lead Left Left Ventricular Ejection Fraction Left Ventricular Function Left Ventricular Remodeling Left ventricular structure Ligation Magnetic Resonance Imaging Mechanics Mediating Medical Membrane Modeling Molecular Morbidity - disease rate Myocardial Myocardial Infarction Myofibroblast Myosin Heavy Chains Operative Surgical Procedures Organ Outcome Patients Play Process Production Protein-Serine-Threonine Kinases Public Health Quality of life Rattus Receptor Signaling Regulation Research Risk Factors Role Signaling Molecule Smooth Muscle Actin Staining Method Stimulus Stretching Testing Therapeutic Time Tissues Treatment Efficacy Up-Regulation Ventricular Ventricular Function Ventricular Remodeling Viral Genes Work adenoviral-mediated improved in vivo inhibitor/antagonist mortality mutant novel novel therapeutics outcome forecast overexpression pressure prevent promoter reconstruction response

项目摘要

DESCRIPTION (provided by applicant): Despite complete revascularization by coronary artery bypass grafting (CABG), long-term survival is markedly inferior for patients who present with depressed left ventricular function post-myocardial infarction. Adverse or maladaptive ventricular remodeling can continue following revascularization and appears to be an important risk factor for poor long-term outcomes after CABG with progression to HF. Cardiac fibroblasts (CF) make up 60-70% of the total cell mass of the heart and play a critical role in regulating normal myocardial function and in the adverse remodeling that occurs with myocardial infarction and the transition to HF. Excessive collagen deposition by CF leads to myocardial stiffening, diastolic dysfunction, and overload of the heart, likely as a consequence of transformation of quiescent fibroblasts responsible for basal extracellular matrix (ECM) homeostasis to activated myofibroblasts (myoFb). Approaches to inhibit this transformation are needed in tissues, such as the heart, where excessive ECM production by CF leads to fibrosis and remodeling which is a precursor to HF. Recent work has demonstrated that increased intracellular cAMP and downstream activation of cAMP-dependent protein kinase (PKA) can inhibit myoFb formation and collagen synthesis in vitro. The primary mechanism for cAMP production in CF is through stimulation of membrane-bound 22-adrenergic receptors which couple to adenylyl cyclase. Recent data from our laboratory show that 2-adrenergic receptor (2-AR) signaling and cAMP production are severely impaired in CF isolated from ventricles of patients with advanced HF and may be a critical underlying mechanism for myoFb formation and increased ECM deposition. We have found that G protein-coupled receptor kinase-2 (GRK2), a serine-threonine kinase that phosphorylates and uncouples agonist-occupied 2-ARs, is robustly expressed in CF and GRK2 activity is significantly upregulated in chronic HF. The long-term goal of this project is to specifically delineate the roles of 2-AR signaling and GRK2 in adult CF transformation to myoFb with the aim of inhibiting or minimizing pathological fibrosis that can lead to HF post-myocardial infarction despite successful revascularization. Our central hypothesis is that impaired 2-AR signaling, as a result of increased GRK2 activity, mediates CF to myoFb transformation and increases ECM synthesis. Thus, impaired CF 2-AR signaling promotes maladaptive remodeling and progressive cardiac dysfunction contributing to HF. This will be tested using molecular approaches to knockdown and over express GRK2 in CF isolated from normal and failing human ventricles to investigate the role of GRK2 in regulating CF activation. In vivo studies will be performed in a rat myocardial infarction model using adeno-associated viral gene transfer of a mini-gene inhibitor of GRK2 in a CF-specific manner to achieve long-term expression and evaluate potential therapeutic efficacy in inhibiting adverse remodeling and improving cardiac function and survival. Inhibition of GRK2 activity has important therapeutic promise in this disease process and may represent a novel adjunctive therapy at the time of CABG. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the discovery of a novel adjunctive therapy which could be delivered at the time of coronary artery bypass surgery to inhibit the potential transition to heart failure in patients who have suffered a pre-operative myocardial infarction could lead to significantly greater quality of life and long-term survival. This research may also be relevant to preventing fibrosis of other organs which also contribute to significant morbidity and mortality.

描述（由申请人提供）：尽管冠状动脉搭桥术（CABG）完全血运重建（CABG），但对于腰部梗死后左心室功能抑郁症的患者，长期生存率显着较低。血运重建后可能会继续进行不良或不良的心室重塑，并且似乎是CABG后长期不良结局的重要危险因素，并发展为HF。心脏成纤维细胞（CF）占心脏总细胞质量的60-70％，在调节正常心肌功能以及在心肌梗塞和HF过渡时发生的不良重塑中起关键作用。 CF通过过度的胶原蛋白沉积导致心肌僵硬，舒张功能障碍和心脏过载，这可能是由于静止成纤维细胞转变而导致基础外基质基质（ECM）稳态转化为活化的肌纤维细胞（Myofb）。在组织（例如心脏）中需要抑制这种转化的方法，在这种组织中，CF产生的ECM产生过多会导致纤维化和重塑，这是HF的前体。最近的工作表明，cAMP依赖性蛋白激酶（PKA）的细胞内cAMP和下游激活增加可以在体外抑制MyOFB的形成和胶原蛋白合成。 CF营地生产的主要机制是刺激膜结合的22-肾上腺素能受体，这些受体将伴侣与腺苷酸环化酶相对生。我们实验室的最新数据表明，从患有晚期HF的患者的心室中分离出的CF中，2-肾上腺素受体（2AR）信号传导和cAMP产生严重受损，可能是MyOFB形成和ECM沉积增加的关键基础机制。我们已经发现，G蛋白偶联受体激酶-2（GRK2）是一种丝氨酸 - 苏氨酸激酶，在CF和GRK2活性中强烈表达磷酸化和Uncopeles磷酸化和Uncoperips agonist agonist型激动剂激酶，在慢性HF中显着上调了GRK2活性。该项目的长期目标是特异性地描绘了2 AR信号传导和GRK2在成人CF转化为MyOFB中的作用，目的是抑制或最小化病理纤维化，这可能导致HF后脊髓杆后梗死，尽管成功进行了血运重建。我们的中心假设是，由于GRK2活性的增加，受损的2-AR信号传导介导了CF为MyOFB转化并增加了ECM合成。因此，CF 2AR信号传导受损可促进适应不良的重塑和导致HF的进行性心脏功能障碍。这将通过从正常和失败的人心室中分离出的CF中的分子方法来测试这一点，以研究GRK2在调节CF激活中的作用。体内研究将在大鼠心肌梗塞模型中使用腺相关的病毒基因转移，以CF特异性方式将GRK2的迷你基因抑制剂转移，以实现长期表达，并评估潜在的治疗功效，以抑制不良重塑和改善心脏功能和改善心脏功能和生存。 GRK2活性的抑制在此疾病过程中具有重要的治疗前景，并且可能代表CABG时的一种新型辅助治疗。公共卫生相关性：拟议的研究与公共卫生有关，因为在冠状动脉搭桥手术时发现了一种新型的辅助疗法，可以抑制遭受术前心肌梗死的患者的潜在过渡到心力衰竭的过渡，这可能会导致更大的质量和长期的生存质量和长期生存。这项研究也可能与防止其他器官的纤维化有关，这也有助于大量发病率和死亡率。