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

• 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
• 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

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.

摘要 心力衰竭(HF)是一种全球性的健康威胁，其发病率正在上升。目前对心力衰竭的治疗主要是直接的 在不适应的心脏外神经荷尔蒙回路的“一刀切”的方法。有证据表明 心肌燃料和能量代谢紊乱导致心力衰竭早期，导致恶性循环 能量匮乏和收缩功能障碍。我们进行了心肌代谢组学和蛋白质组学研究 明确界定的早期心力衰竭小鼠模型和心力衰竭末期小鼠模型。结果是 在这些侧写研究中，已经确定了HF中的蛋白质和代谢物特征，这些特征表明瓶颈 在心脏脂肪酸氧化(FAO)中，TCA循环的乙酰辅酶A的主要来源以及 肥厚和衰竭的心脏中酮体氧化增加。最近，我们发现 增加酮体，3-羟基丁酸酯(3OHB)到心脏的输送，延缓心衰的发展 在小鼠和犬类的跑动模型中。然而，解释这种现象的生物学机制 3OHB的心脏保护作用尚不清楚。例如，这些有益的影响是心脏自主的吗？是 3OHB提供燃料还是通过其他机制发挥作用？此MPI提案旨在测试 一种假说认为增加心肌酮通过提供一种 更容易氧化的燃料，用于线粒体ATP的生产。为了解决这个假设：1)我们将探索 3OHB在心力衰竭发生发展过程中的心脏特异性有益作用。一组口服液的疗效 给予酮酯对心脏功能和病理重塑的影响将在野生型和 心脏特异的Bdh1缺陷小鼠(心脏不能氧化3OHb)在心力衰竭的发展过程中。此外, 将评估30HB对心肌细胞收缩能力和钙瞬变的细胞自主影响 从患有心力衰竭的人中分离出来；2)我们将研究3OHB作为心肌燃料在其有益作用中的作用 评价R-30HB(氧化)与S-30HB(未氧化)对病理性心脏重构的影响 3)我们将开发和验证策略，以增加 心肌30HB给药作为治疗大动物模型心力衰竭的一种策略 R-30OHB和S-30HB对犬心动过速模型心脏血流动力学和底物代谢的影响 进行性高频。最后，3OHB作为治疗剂的潜力将通过比较影响而被发掘。 在心力衰竭发作前后进行给药，并测试口服30HB酯。计划中的研究将 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 增加酮体向心脏递送作为一种新的治疗方法的临床评估。

项目成果

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