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: 9290197
• 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/9290197
• 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; 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.

项目概要 慢性肾脏病 (CKD) 患者经常会出现以舒张性心肌病为特征的“尿毒症”心肌病。 尽管现代疗法 我们已经描述了强心类固醇（CTS）在神经激素阻断中的核心机制作用。 肾脏损伤后激活促炎和促纤维化途径，从而加剧尿毒症 CTS 是一类类固醇激素，包括蟾蜍二烯内酯，例如海蟾蜍配基和 远华蟾蜍精在体积膨胀的情况下（例如 CKD）显着升高，并且可以直接 通过 Na+/K+-ATP 酶结合并发出信号，导致炎症和心脏纤维化。 对氧磷酶 (PON) 是水解内酯酶，根据异构体，其要么在 肝脏和大修与高密度脂蛋白结合或在组织水平上在细胞内表达。 初步实验和临床数据表明内酯酶活性降低之间存在关联 PON 和 CKD 中心脏疾病的严重程度和进展的潜在心脏保护作用。 现在，我们第一次发现了新的机制相互作用。 PON 的内酯酶活性将 CTS 水解为对氧磷酶和内源性 CTS。 它们的开环形式与天然 CTS 不同，不能刺激胶原蛋白的形成。 该提案的总体目标是测试以下假设：PON 的心脏保护作用可以阻止进行性心脏病 CKD 中的纤维化和舒张功能障碍，其机制是通过调节致病性而发生的 我们的研究将定义 PON 和 PON 的新型内源底物。 首次建立CTS活性减弱心脏重塑的反调节机制 肾损伤后。