Protective signaling mechanisms of the alpha1A-adrenoceptor

α1A-肾上腺素受体的保护性信号传导机制

• 批准号: 7982876
• 负责人: DIANNE M PEREZ
• 金额: $ 39.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982876
• 关键词: Adrenergic Agonists; Adrenergic Antagonists; Adrenergic Receptor; Affinity; Animal Model; Antihypertensive Agents; Apoptosis; Apoptotic; Binding; Blood Pressure; Cardiac; Cardiovascular Physiology; Caspase; Catecholamines; Chronic; Clinical; Clinical Trials; Coupling; Cytokine Activation; Data; Development; Drug abuse; Functional disorder; G-Protein-Coupled Receptors; Heart; Heart failure; Hypertrophy; IL6 gene; Imidazolines; In Vitro; Inflammation; Injury; Interleukin-6; Ischemia; Laboratories; Lead; Light; Lipids; MAPK14 gene; Mediating; Mus; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Nerve Degeneration; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Positioning Attribute; Prostatic Diseases; Prostatic hypertrophy; Protein Isoforms; Proteins; Proteomics; Publishing; Receptor Signaling; Regulation; Regulation of Apoptosis Pathway; Research; Role; STAT3 gene; Signal Pathway; Signal Transduction; Sympathetic Nervous System; Transgenic Mice; Work; carvedilol; caspase-3; comparative; effective therapy; in vivo; in vivo Model; mortality; novel; novel therapeutics; preconditioning; prevent; public health relevance; receptor coupling; scaffold

DESCRIPTION (provided by applicant): Our objective is to understand differential signal transduction paradigms by which a1 -adrenergic receptor (AR) subtypes mediate protection versus damage in the heart. a1-AR subtypes (a1A, a1B and a1D) are G protein-coupled receptors that mediate the sympathetic nervous system by binding catecholamines. However, little is known about specific subtype functions. Our research has suggested that a1-AR signaling pathways may contribute to either cardioprotection or damage. a1-AR antagonists were initially thought to be useful in treating heart failure due to sympathetic overload. However, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the use of a non-selective a1-AR antagonist worsened heart failure and increased mortality. In contrast, carvedilol, an antagonist of a1- and ¿-ARs but with higher affinity for the a1B-AR subtype, provides an effective treatment for chronic heart failure, suggesting that subtype-specific signaling may contribute to these differential effects of a1-AR blockade. Because of the use of a1-AR antagonists in prostatic disease, its increasing potential for treating drug abuse and neurodegeneration, determining the role of a1-AR subtypes in the heart has very important clinical implications. Our laboratory had made unique transgenic mice of the a1-AR subtypes and demonstrated differential regulation of cardiovascular function. We have published that the a1A-AR but not the a1B-AR protected the heart from ischemic injury. Chronic a1B-AR stimulation resulted in heart dysfunction, and inflammation. We have determined unique pathways that are differentially regulated by the a1-AR subtypes, such as apoptosis, STAT3 activation, and cytokine secretion, which may explain how the a1-AR subtypes differentially control cardiac adaptation. Our research may lead to the development of new therapeutic strategies to treat heart failure and ischemia. This proposal focuses on a1-AR subtypes in the heart and differential RGS/GRK scaffolds coupling to different PKC/MAPK isoforms, explaining why a1A-AR stimulation is protective while chronic stimulation of the a1B-AR promotes cardiac damage. PUBLIC HEALTH RELEVANCE: This proposal will demonstrate and determine the mechanism by which the a1A- adrenergic receptor can protect the heart against ischemia and induce an adaptive hypertrophy that protects against apoptosis. In light of clinical trials which indicate that blockage of a1-ARs is deleterious for heart failure, but are commonly used to treat prostatic hyperplasia, we need to determine the exact roles of the a1-AR subtypes in cardiac regulation using animal models that will give definitive answers.

描述（由申请人提供）：我们的目的是了解α 1-肾上腺素能受体（AR）亚型介导心脏保护与损伤的不同信号转导模式。a1-AR亚型（a1 A、a1 B和a1 D）是G蛋白偶联受体，其通过结合儿茶酚胺来介导交感神经系统。然而，对特定的子类型函数知之甚少。我们的研究表明，α 1-AR信号通路可能有助于心脏保护或损伤。最初认为α 1-AR拮抗剂可用于治疗由于交感神经超负荷引起的心力衰竭。然而，在抗高血压和降脂治疗预防心脏病发作试验中，使用非选择性α 1-AR拮抗剂使心力衰竭恶化并增加死亡率。与此相反，卡维地洛，一种α 1-和β-AR的拮抗剂，但对α 1B-AR亚型具有更高的亲和力，为慢性心力衰竭提供了有效的治疗，这表明亚型特异性信号传导可能有助于α 1-AR阻断的这些差异效应。由于α 1-AR拮抗剂在前列腺疾病中的使用，其治疗药物滥用和神经变性的潜力增加，确定α 1-AR亚型在心脏中的作用具有非常重要的临床意义。我们的实验室已经制造了独特的α 1-AR亚型转基因小鼠，并证明了心血管功能的差异调节。我们已经发表了a1 A-AR而不是a1 B-AR保护心脏免受缺血性损伤。慢性a1 B-AR刺激导致心脏功能障碍和炎症。我们已经确定了独特的途径，差异调节的α 1-AR亚型，如细胞凋亡，STAT 3激活，细胞因子分泌，这可能解释了如何差异控制心脏适应α 1-AR亚型。我们的研究可能会导致新的治疗策略的发展，以治疗心力衰竭和缺血。该提案的重点是心脏中的a1-AR亚型和与不同PKC/MAPK亚型偶联的差异RGS/GRK支架，解释了为什么a1 A-AR刺激具有保护作用，而a1 B-AR的慢性刺激促进心脏损伤。 公共卫生相关性：该提议将证明和确定α 1A-肾上腺素能受体可保护心脏免受缺血并诱导防止细胞凋亡的适应性肥大的机制。鉴于临床试验表明α 1-AR的阻断对心力衰竭有害，但通常用于治疗前列腺增生，我们需要使用动物模型确定α 1-AR亚型在心脏调节中的确切作用，这将给出明确的答案。