Targeting Ketone Metabolism as a Novel Heart Failure Therapy

以酮代谢为目标的新型心力衰竭疗法

基本信息

批准号：
10592265
负责人：
DANIEL PATRICK KELLY
金额：
$ 80.26万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592265
关键词：
Accounting Acetyl Coenzyme A Acute Address Animal Model Biological Calcium Canis familiaris Cardiac Cardiac Myocytes Cells Chronic Citric Acid Cycle Development Disease Esters Fatty Acids Functional disorder Future Glucose Goals Heart Heart failure Human Hypertrophy Incidence Ketone Bodies Ketones Metabolic Metabolism Mitochondria Modeling Mus Myocardial Oral Oral Administration Pathologic Peripheral Resistance Prevalence Prevention Preventive Production Proteins Proteomics Role Source Starvation Supplementation Testing Therapeutic Therapeutic Agents Treatment Failure Ventricular Function beta-Hydroxybutyrate canine model cardioprotection design efficacy evaluation fatty acid oxidation global health heart function hemodynamics improved insight metabolomics mouse model novel novel therapeutic intervention novel therapeutics oxidation pre-clinical assessment response

项目摘要

SUMMARY The incidence of heart failure (HF), a global health threat, is growing. Current therapies for HF are largely directed at maladaptive extra-cardiac neurohormonal circuits in a “one size fits all” approach. Evidence has emerged that myocardial fuel and energy metabolic disturbances contribute to the early stages of HF leading to a vicious cycle of energy starvation and contractile dysfunction. We have conducted myocardial metabolomic and proteomic profiling in well-defined mouse models of early stage HF and in the end-stage failing human heart. The results of these profiling studies have identified protein and metabolite signatures in HF that are indicative of bottlenecks in cardiac fatty acid oxidation (FAO), the chief source of acetyl-CoA for the TCA cycle along with evidence for increased ketone body oxidation in the hypertrophied and failing heart. More recently, we have found that increasing delivery of the ketone body, 3-hydroxybutyrate (3OHB) to heart, retards the development of HF in mice and in a canine tachypacing model. However, the biological mechanisms accounting for the cardioprotective effect of 3OHB are unknown. For example, are these beneficial effects cardiac autonomous? Is 3OHB providing a fuel or does it act via other mechanisms? This MPI proposal is designed to test the hypothesis that increasing myocardial ketones reduces pathological cardiac remodeling by providing a more readily oxidizable fuel for mitochondrial ATP production. To address this hypothesis: 1) we will probe the cardiac-specific beneficial actions of 3OHB during the development of HF. The efficacy of a panel of orally administered ketone esters on cardiac function and pathological remodeling will be assessed in wild-type and cardiac-specific Bdh1-deficient mice (unable to oxidize 3OHB in heart) during development of HF. In addition, the cell-autonomous impact of 3OHB on contractility and calcium transients will be assessed in cardiac myocytes isolated from humans with HF; 2) we will investigate the role of 3OHB as a myocardial fuel in its beneficial actions on pathologic cardiac remodeling by assessing the efficacy of R-3OHB (oxidized) vs S-3OHB (unoxidized) ketone esters on the development of HF in mice; and 3) we will develop and validate strategies to increase myocardial 3OHB delivery as a therapeutic strategy for HF in a large animal model by assessing the effects of R-3OHB and S-3OHB on cardiac hemodynamics and substrate metabolism in a canine tachypacing model of progressive HF. Lastly, the potential of 3OHB as a therapeutic agent will be explored by comparing the impact of administration before and after the onset of HF as well as testing oral 3OHB esters. The planned studies will provide important new insight into the mechanisms whereby 3OHB ameliorates HF and will provide in-depth pre- clinical assessment of increasing delivery of ketone bodies to heart as a novel therapeutic.

概括全球健康威胁的心力衰竭事件正在增长。 HF的当前疗法主要针对在不良适应性的心外神经激素电路中，“一种尺寸适合所有人”的方法。有证据表明心肌燃料和能源代谢灾害有助于HF的早期阶段，导致恶性循环能量饥饿和收缩功能障碍。我们进行了心肌代谢组和蛋白质组学在明确定义的HF的小鼠模型以及人类心脏失败的末期中进行分析。结果在这些分析研究中，已经确定了HF中的蛋白质和代谢物特征在心脏脂肪酸氧化（FAO）中，TCA周期的乙酰辅酶A的主要来源以及证据肥厚和心脏衰竭的酮体氧化增加。最近，我们发现酮体的递送，3-羟基丁酸（3OHB）的递送到心脏，降低了HF的发展小鼠和犬类tachypacing模型。但是，生物学机制占 3OHB的心脏保护作用尚不清楚。例如，这些有益的心脏自主效果吗？是 3OHB提供燃料还是通过其他机制起作用？该MPI建议旨在测试增加心肌酮的假设可以通过提供一种来减少病理心脏重塑线粒体ATP产生的更容易氧化的燃料。要解决这一假设：1）我们将证明 3OHB在HF发展过程中的心脏特异性有益作用。口服面板的效率在野生型和 HF发育过程中心脏特异性的BDH1缺陷小鼠（无法氧化3OHB）。此外，将在心肌细胞中评估3OHB对收缩性和钙瞬变的细胞自主影响用HF与人类隔离； 2）我们将调查3OHB作为心肌燃料的作用通过评估R-3OHB（氧化）与S-3OHB的效率（非氧化），对病理心脏重塑酮酯关于小鼠HF的发展； 3）我们将制定并验证策略以增加心肌3OHB通过评估大型动物模型中HF的治疗策略 R-3OHB和S-3OHB在心脏血液动力学和底物代谢的犬类速度模型中渐进的HF。最后，将通过比较影响来探索3OHB作为治疗剂的潜力 HF发作前后的给药以及测试口服3OHB酯。计划的研究将对3OHB改善HF的机制提供重要的新见解，并将提供深入的前将酮体递送到心脏的临床评估是一种新的疗法。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metabolomic Signatures of Myocardial Glucose Uptake on Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography.

DOI：
10.1016/j.jacbts.2022.09.011
发表时间：
2022-12
期刊：
JACC-BASIC TO TRANSLATIONAL SCIENCE
影响因子：
9.7
作者：
Vidula, Mahesh K.;Kelly, Daniel P.;Md, Zoltan Arany;Margulies, Kenneth B.;Shah, Svati H.;Cappola, Thomas P.;Bravo, Paco E.;Selvaraj, Senthil
通讯作者：
Selvaraj, Senthil