CHRONO-MECHANISMS of CARDIOMETABOLIC PHARMACOLOGY

心脏代谢药理学的时间机制

• 批准号: 10271560
• 负责人: Mattia Quattrocelli
• 金额: $ 39.75万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10271560
• 关键词: ARNTL gene; Ablation; Acute; Alleles; Antidiabetic Drugs; Binding; Biological Markers; Branched-Chain Amino Acids; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Catabolism; Chronic; Clinical Trials; Corticosterone; Data; Depressed mood; Diabetes Mellitus; Diabetic mouse; Disease; Dose; Glucocorticoid Receptor; Glucocorticoids; Glucose; Half-Life; Health; Heart; Hormones; Impairment; Injury; Insulin Resistance; Intake; Knock-in; Link; Low Cardiac Output Syndrome; Mediating; Metabolic; Metabolic acidosis; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Molecular; Mus; Muscle; Nuclear Translocation; Nutrient; Obesity; Organ; Patients; Pharmacology; Phase; Prednisone; Prodrugs; Publishing; Receptor Activation; Regimen; Role; Steroids; Striated Muscles; Testing; Time; Transgenic Mice; Transgenic Model; base; cardiometabolism; circadian; circadian pacemaker; circadian regulation; combat; diabetic; diabetic cardiomyopathy; epigenomics; flexibility; heart circulation; heart function; heart metabolism; improved; insulin sensitivity; novel; nutrient metabolism; oxidation; programs; receptor; receptor sensitivity; response; transcription factor; uptake; virtual

PROJECT SUMMARY Glucocorticoid steroids are conserved pleiotropic hormones regulating the circadian cycle of energy utilization and storage in virtually all our organs. Nutrient metabolism in the heart is critical to adapt the high energy demand to circadian oscillations and/or diseased states like diabetic cardiomyopathy. Glucocorticoids exert their effects through the glucocorticoid receptor (GR), which is required for normal heart function. Indeed, synthetic glucocorticoids are routinely used to rescue cardiac conditions of metabolic acidosis and depressed function, such as low cardiac output syndrome. However, chronic GR over-stimulation with synthetic glucocorticoids promotes metabolic syndrome and cardiovascular diseases. Thus, the molecular and circadian effects of synthetic glucocorticoids and their receptor on cardiac metabolism are still unresolved. Using dystrophic mice as model of chronic striated muscle injury, I discovered that intermittent dosing (once-weekly) of glucocorticoids boosts nutrient utilization and insulin sensitivity in dystrophic muscle and heart. Here I postulate that intermittent glucocorticoids improve cardiometabolic health beyond the dystrophic heart and can be exploited to combat diabetic cardiomyopathy. In mice, oscillations of endogenous corticosterone and circadian clock factors create a critical time window for acute GR responsiveness to pharmacological activation in the early diurnal phase. Indeed, I found that diurnal – but not nocturnal – regimens of intermittent prednisone improved cardiac function and metabolism in wildtype hearts. Diurnal administration was critical for the prednisone-driven GR program to boost mitochondrial capacity and activate the metabolic regulators KLF15 and AMPK. Also, diurnal prednisone reduced 3-hydroxyisobutyrate (3-HIB), biomarker of impaired catabolism of branched chain amino acids (BCAA) and insulin resistance in diabetes. Thus, I hypothesize that chrono- pharmacology with diurnal glucocorticoids promotes cardiometabolic health through GR, KLF15 and AMPK activation, and reduces 3-HIB as biomarker of metabolic rescue in diabetic cardiomyopathy. To test this hypothesis, we will articulate the project to test three complementary mechanisms: in Aim 1, we will test the requirement for GR and the clock factor BMAL in the effects of diurnal prednisone on mitochondrial capacity in heart; in Aim 2, we will define requirement and epigenomic mechanisms for the GR-activated KLF15 in reshaping nutrient utilization in cardiomyocytes in response to prednisone chrono-dosing; in Aim 3, we will determine the role of AMPK and BCAA oxidation in mediating the effects of diurnal intermittent prednisone on metabolic flexibility and 3-HIB levels in diabetic cardiomyopathy. This proposal charts a novel path to cardiometabolic rescue by exploiting the circadian-gated response to synthetic glucocorticoids in heart. Defining unprecedented mechanisms of interplay between glucocorticoid cascades and circadian clock, the project will provide evidence for time-restricted intermittent dosing as “flip switch” of glucocorticoid action in heart metabolism, converting these drugs from “pro-diabetic” to “anti-diabetic” in cardiometabolic health.

项目概要 糖皮质激素类固醇是调节能量利用昼夜节律的保守多效激素 并储存在我们几乎所有的器官中。心脏的营养代谢对于适应高能量至关重要 对昼夜节律波动和/或糖尿病心肌病等疾病状态的需求。糖皮质激素发挥作用 它们通过糖皮质激素受体（GR）发挥作用，而糖皮质激素受体是正常心脏功能所必需的。的确， 合成糖皮质激素通常用于挽救代谢性酸中毒和抑郁症等心脏病 功能，例如低心输出量综合征。然而，合成的慢性 GR 过度刺激 糖皮质激素会促进代谢综合征和心血管疾病。因此，分子和昼夜节律 合成糖皮质激素及其受体对心脏代谢的影响仍未解决。使用 营养不良小鼠作为慢性横纹肌损伤模型，我发现间歇给药（每周一次） 糖皮质激素可提高营养不良的肌肉和心脏的营养利用率和胰岛素敏感性。在这里我 假设间歇性糖皮质激素可以改善营养不良心脏以外的心脏代谢健康，并且可以 可用于对抗糖尿病性心肌病。在小鼠中，内源性皮质酮和 生物钟因素为 GR 对药理激活的急性反应创造了一个关键的时间窗口 在昼夜早期。事实上，我发现白天（而不是夜间）间歇性泼尼松疗法 改善野生型心脏的心脏功能和新陈代谢。每日给药对于 泼尼松驱动的 GR 程序可增强线粒体能力并激活代谢调节剂 KLF15 和 AMPK。此外，每日泼尼松可降低分解代谢受损的生物标志物 3-羟基异丁酸 (3-HIB) 支链氨基酸（BCAA）和糖尿病胰岛素抵抗的关系。因此，我假设时间 每日糖皮质激素的药理学通过 GR、KLF15 和 AMPK 促进心脏代谢健康 激活，并减少 3-HIB 作为糖尿病心肌病代谢救援的生物标志物。为了测试这个 假设，我们将阐明该项目来测试三种互补机制：在目标 1 中，我们将测试 昼夜强的松对线粒体能力影响中对 GR 和时钟因子 BMAL 的需求 心;在目标 2 中，我们将定义 GR 激活的 KLF15 的要求和表观基因组机制 重塑心肌细胞的营养利用以响应泼尼松计时给药；在目标 3 中，我们将 确定 AMPK 和 BCAA 氧化在介导昼间间歇性泼尼松影响中的作用 糖尿病心肌病的代谢灵活性和 3-HIB 水平。该提案开辟了一条新颖的道路 通过利用心脏对合成糖皮质激素的昼夜门控反应来挽救心脏代谢。 定义了糖皮质激素级联和生物钟之间前所未有的相互作用机制， 该项目将为限时间歇给药提供证据，作为糖皮质激素作用的“翻转开关” 心脏代谢，将这些药物在心脏代谢健康方面从“促糖尿病”转变为“抗糖尿病”。