Counter regulatory mechanisms of cardiotonic steroids in cardio-renal syndrome

强心类固醇治疗心肾综合征的反调节机制

• 批准号: 9898432
• 负责人: David Joseph Kennedy
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898432
• 关键词: Affect; Arylesterase; Attenuated; Binding; Cardiac; Cardiac Death; Cardiac Glycosides; Cardiovascular system; Chronic Kidney Failure; Clinical Data; Collagen; Data; Development; Disease Progression; Enzymes; Event; Exhibits; Family; Fibrosis; Functional disorder; Future; Genetic; Gluconolactonase; Goals; Heart Diseases; High Density Lipoproteins; Hydrolysis; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Infusion procedures; Kidney; Knock-out; Knockout Mice; Lead; Left Ventricular Hypertrophy; Liver; Mediating; Morbidity - disease rate; Mus; Na(+)-K(+)-Exchanging ATPase; Nephrectomy; Pathway interactions; Patients; Protein Isoforms; Regulation; Risk; Role; Severity of illness; Signal Transduction; Syndrome; Testing; Therapeutic; Time; Tissues; Wild Type Mouse; aryldialkylphosphatase; bufadienolide; cardioprotection; clinical development; coronary fibrosis; fight against; gene therapy; in vivo; lipid metabolism; marinobufagenin; mortality; mouse model; novel; oxidant stress; public health relevance; safety and feasibility; steroid hormone; treatment strategy; uremic cardiomyopathy

PROJECT SUMMARY Patients with chronic kidney disease (CKD) often develop a “uremic” cardiomyopathy characterized by diastolic dysfunction, left ventricular hypertrophy, and cardiac remodeling, despite contemporary therapies of neurohormonal blockade. We have described a central mechanistic role of cardiotonic steroids (CTS) in activating pro-inflammatory and pro-fibrotic pathways following renal insult that potentiate this uremic cardiomyopathy. CTS are a family of steroid hormones including bufadienolides such as marinobufagenin and telocinobufagin which are significantly elevated in volume expanded conditions such as CKD and can directly lead to inflammation and cardiac fibrosis upon binding and signaling through the Na+/K+-ATPase. Paraoxonases (PON) are hydrolytic lactonase enzymes that, depending on isoform, are either generated in the liver and circulate bound to high-density lipoprotein or are expressed intracellularly at the tissue level. Our preliminary experimental and clinical data demonstrate an association between diminished lactonase activities of PON and cardiac disease severity and progression in CKD. Yet the underlying cardioprotective mechanism(s) are largely unknown. Now, for the first time, we have identified novel mechanistic interactions between paraoxonases and endogenous CTS. Interestingly, the lactonase activities of PON hydrolyze CTS to their open-ring forms which, unlike native CTS, are incapable of stimulating collagen formation. Hence, the overall goal of this proposal is to test the hypotheses that cardioprotection by PON can deter progressive cardiac fibrosis and diastolic dysfunction in CKD, and that the mechanism occurs via modulation of pathogenetic pathways induced by endogenous CTS. Our studies will define a novel endogenous substrate for PON and establish for the first time a counter-regulatory mechanism of CTS activities in attenuating cardiac remodeling following renal insult.

项目摘要 患有慢性肾脏疾病（CKD）的患者通常会出现以舒张期为特征的“尿毒症”心肌病 功能障碍，左心室肥大和心脏重塑，dospite现代疗法 神经激素阻滞。我们已经描述了心差类固醇（CTS）在 肾损伤后激活促炎和促纤维化途径，潜在这种尿毒症 心肌病。 CT是一个类固醇恐怖剂的家族，包括Marinobufagenin和 telocinobufagin在体积膨胀条件（例如CKD）中显着升高，可以直接 通过Na+/K+-ATPase结合和信号传导后，导致炎症和心脏纤维化。 二氧蛋白酶（PON）是水解乳酸酶酶，取决于同工型，要么在 肝脏并循环与高密度脂蛋白结合或在组织水平上细胞内表达。我们的 初步实验和临床数据表明，腹腔酶活性降低 CKD中PON和心脏病的严重程度和进展。然而，基础的心脏保护 机理在很大程度上未知。现在，我们第一次确定了新型的机械互动 在多氧酶和内源性CT之间。有趣的是，PON的LACTONASE活性将CTS水解为 它们的开环形式与天然CT不同，无法刺激胶原蛋白形成。因此， 该提案的总体目标是检验pon心脏保护可以确定心脏的假设 CKD中的纤维化和舒张功能障碍，该机理是通过致病性调节而发生的 内源性CT诱导的途径。我们的研究将定义一个新型的pON内源性底物和 首次建立CTS活动的反调节机制在减弱心脏重塑时 跟随肾脏侮辱。