Mechanisms of sulfonylurea receptor mediated cardiomyopathy

磺酰脲类受体介导的心肌病的机制

• 批准号: 8976166
• 负责人: JONATHAN C MAKIELSKI
• 金额: $ 61.62万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976166
• 关键词: ATP-Binding Cassette Transporters; Ablation; Adult; Alternative Splicing; Binding; Blood Vessels; CRSP3 gene; Cantu syndrome; Cardiac; Cardiac Myocytes; Cardiomegaly; Cardiomyopathies; Cell Respiration; Cells; Characteristics; Clinical; Complex; Consumption; Coronary artery; Couples; Data; Diabetes Mellitus; Dilated Cardiomyopathy; Disease; Drug Design; Drug usage; Energy Supply; Equilibrium; Exons; Genes; Genetic; Genetically Engineered Mouse; Glucose; Glyburide; Growth; Heart; Heart failure; Human; Hypertension; Integral Membrane Protein; Ischemia; Ischemic Preconditioning; Length; Life; Link; Mediating; Membrane Potentials; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Mutation; Myocardial Ischemia; Myocardium; Neonatal; Newborn Infant; Nucleotides; Pathway interactions; Perinatal mortality demographics; Pharmaceutical Preparations; Potassium; Potassium Channel; Production; Proteins; Regulation; Reperfusion Injury; Reporting; Role; Sarcomeres; Signal Transduction; Source; Spasm; Stress; Sulfonylurea Compounds; Testing; Tissues; Transgenic Organisms; Ventricular; cardiovascular disorder risk; cardiovascular risk factor; density; diabetic; fatty acid oxidation; glucose metabolism; improved; novel; nucleotide binding fold; nutrition; overexpression; preconditioning; public health relevance; research study; response; sudden cardiac death; sulfonylurea receptor

DESCRIPTION (provided by applicant): ATP-sensitive potassium (KATP) channels response to the intracellular energy state of the cell through directly nucleotide binding. KATP channels sense intracellular ADP content and, in response, regulate membrane potential. The major KATP regulatory component found in the ventricular cardiomyocyte is the sulfonylurea receptor (SUR)-2, encoded by the Abcc9 gene. Like other ABC transporter proteins, SUR2 is a multi- transmembrane protein with two nucleotide-binding folds. Glyburide, a sulfonylurea antagonist, is used commonly to treat diabetes, although this class of medications has been reported to increase cardiovascular risk in diabetics. The clinical use of drugs that act through the SURs, as well as the possibility to develop additional agents that utilize these pathways, argues for improved understanding of SURs and their role especially in high energy demand tissue like the heart. Mutations in the Abcc9/SUR2 gene cause dilated cardiomyopathy and more recently have been linked to Cantu syndrome, a rare multisystem disorder that includes cardiomegaly (Harakalova et al., 2012; van Bon et al., 2012). The Abcc9 gene undergoes alternative splicing to produce SUR2, a characteristic ATP binding cassette protein, and also a smaller 55 KDa protein, which we termed SUR2- 55. Like SUR2, SUR2-55 can couple with the partner potassium channel but SUR2-55 is enriched in mitochondria. Deletion of the Abcc9 gene in a manner that leaves SUR2-55 intact, leads to coronary artery vascular spasm, hypertension, sudden cardiac death. In contrast, deletion of Abcc9 in a manner that ablate both SUR2 and SUR2-55 leads to neonatal cardiomyopathy in the first 10 days of life. The newborn heart is known to transition from glucose to oxidative metabolism during this window, and this transition is impaired in Abcc9 deleted mice. In separate experiments, we found that transgenic overexpression of SUR-55 in the heart protects the heart from ischemic reperfusion injury. We hypothesize that Abcc9-encoded proteins, through KATP channels, contribute to the metabolic balance especially under stress conditions such as the newborn heart and in ischemic myocardium. Ablation of Abbc9 in the newborn and adult myocardium will be used to define SUR2 complexes and their role in the heart.

描述（由申请人提供）：atp敏感钾（KATP）通道通过直接核苷酸结合对细胞内能量状态作出反应。KATP通道感知细胞内ADP含量，并相应地调节膜电位。在心室心肌细胞中发现的主要KATP调节成分是磺酰脲受体(SUR)-2，由Abcc9基因编码。与其他ABC转运蛋白一样，SUR2是一种多跨膜蛋白，具有两个核苷酸结合折叠。格列本脲是一种磺脲类拮抗剂，通常用于治疗糖尿病，尽管有报道称这类药物会增加糖尿病患者的心血管风险。临床使用的药物通过这些途径起作用，以及开发利用这些途径的其他药物的可能性，表明需要进一步了解这些途径及其作用，特别是在心脏等高能量需求组织中的作用。Abcc9/SUR2基因突变导致扩张性心肌病，最近与坎图综合征有关，坎图综合征是一种罕见的多系统疾病，包括心脏肥大（Harakalova等人，2012；van Bon等人，2012）。Abcc9基因经过选择性剪接产生SUR2，这是一种典型的ATP结合盒蛋白，也是一种较小的55 KDa蛋白，我们将其命名为SUR2- 55。与SUR2一样，SUR2-55可以与伴侣钾通道偶联，但SUR2-55在线粒体中富集。Abcc9基因的缺失使SUR2-55保持完整，导致冠状动脉血管痉挛、高血压、心源性猝死。相反，Abcc9的缺失同时导致SUR2和SUR2-55的消融，会导致新生儿在出生后10天内出现心肌病。已知新生儿心脏在这一窗口期从葡萄糖代谢转变为氧化代谢，而这种转变在Abcc9缺失的小鼠中受损。在单独的实验中，我们发现在心脏中转基因过表达SUR-55可以保护心脏免受缺血再灌注损伤。我们假设abcc9编码的蛋白，通过KATP通道，促进代谢平衡，特别是在应激条件下，如新生儿心脏和缺血心肌。消融新生儿和成人心肌中的Abbc9将用于确定SUR2复合物及其在心脏中的作用。