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.

概括心力衰竭（HF）是一种全球健康威胁，其发病率正在不断上升，目前的心力衰竭治疗主要是针对的。有证据表明，以“一刀切”的方法治疗适应不良的心外神经激素回路。心肌燃料和能量代谢紊乱导致心力衰竭的早期阶段，从而导致恶性循环我们进行了心肌代谢组学和蛋白质组学研究。对早期心力衰竭和晚期衰竭人类心脏的明确小鼠模型进行分析。这些分析研究中的一些已经确定了 HF 中指示瓶颈的蛋白质和代谢物特征心脏脂肪酸氧化 (FAO) 是 TCA 循环乙酰辅酶 A 的主要来源，并有证据表明最近，我们发现肥大和衰竭的心脏中酮体氧化增加。增加酮体、3-羟基丁酸 (3OHB) 向心脏的输送，可延缓心力衰竭的发生然而，在小鼠和犬类快速起搏模型中，其生物学机制却有所不同。 3OHB 的心脏保护作用尚不清楚，例如，这些有益作用是对心脏的自主作用吗？ 3OHB 提供燃料还是通过其他机制起作用？该 MPI 提案旨在测试假设增加心肌酮通过提供线粒体 ATP 生产更容易氧化的燃料为了解决这个假设：1）我们将探讨。心力衰竭发生过程中 3OHB 对心脏的特异性有益作用一组口服药物的功效。给予酮酯对心脏功能和病理重塑的影响将在野生型和心力衰竭发生期间心脏特异性 Bdh1 缺陷小鼠（无法氧化心脏中的 3OHB）。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从心力衰竭患者中分离出来；2) 我们将研究 3OHB 作为心肌燃料的有益作用通过评估 R-3OHB（氧化）与 S-3OHB（未氧化）的功效来影响病理性心脏重塑酮酯对小鼠心力衰竭发展的影响；3）我们将开发并验证增加的策略通过评估心肌 3OHB 递送作为大型动物模型中 HF 的治疗策略 R-3OHB 和 S-3OHB 对犬快速起搏模型中心脏血流动力学和底物代谢的影响最后，将通过比较 3OHB 的影响来探讨 3OHB 作为治疗药物的潜力。计划中的研究将在 HF 发作之前和之后进行给药以及测试口服 3OHB 酯。为 3OHB 改善心力衰竭的机制提供重要的新见解，并将提供深入的预作为一种新型治疗方法，增加酮体向心脏的输送的临床评估。

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