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.

项目摘要 糖皮质激素是一种保守的多效性激素，调节能量利用的昼夜节律周期 和储存在我们几乎所有的器官中。心脏中的营养代谢对于适应高能量至关重要 昼夜节律振荡和/或糖尿病心肌病等疾病状态的需求。糖皮质激素发挥 它们通过糖皮质激素受体（GR）发挥作用，而GR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等心脏病 功能，如低心排血量综合征。然而，慢性GR过度刺激与合成 糖皮质激素促进代谢综合征和心血管疾病。因此，分子和昼夜节律 合成的糖皮质激素及其受体对心脏代谢的影响仍不清楚。使用 作为慢性横纹肌损伤的模型，我发现间歇给药（每周一次） 在营养不良的肌肉和心脏中，糖皮质激素的使用促进了营养利用和胰岛素敏感性。这里我 假设间歇性糖皮质激素改善了营养不良心脏以外的心脏代谢健康， 用于治疗糖尿病性心肌病在小鼠中，内源性皮质酮和 生物钟因素为药物激活的急性GR反应性创造了一个关键的时间窗口 在白天的早期阶段。事实上，我发现白天--而不是夜间--间歇性强的松治疗方案 改善野生型心脏的心脏功能和代谢。昼夜给药对于 泼尼松驱动的GR程序，以提高线粒体的能力，并激活代谢调节因子KLF 15 和AMPK。此外，昼夜泼尼松减少了3-羟基异丁酸（3-HIB），受损catabolic的生物标志物 支链氨基酸（BCAA）与糖尿病胰岛素抵抗的关系。因此，我推测，时间- 昼夜使用糖皮质激素的药理学通过GR、KLF 15和AMPK促进心脏代谢健康 激活，并减少3-HIB作为糖尿病心肌病中代谢救援的生物标志物。为了验证这一 假设，我们将阐明该项目，以测试三个互补机制：在目标1中，我们将测试 GR和生物钟因子BMAL在泼尼松昼夜作用于线粒体容量中的作用 在目标2中，我们将定义GR激活的KLF 15在心脏中的需求和表观基因组机制。 响应泼尼松定时给药，重塑心肌细胞的营养利用;在目标3中，我们将 确定AMPK和BCAA氧化在介导昼夜间歇性泼尼松对 糖尿病性心肌病患者的代谢灵活性和3-HIB水平。这一提议开辟了一条新的道路， 通过利用心脏中对合成糖皮质激素的昼夜节律门控反应进行心脏代谢拯救。 定义糖皮质激素级联和生物钟之间前所未有的相互作用机制， 该项目将提供证据，证明有时间限制的间歇给药是糖皮质激素作用的“触发开关”， 心脏代谢，将这些药物从“促糖尿病”转变为“抗糖尿病”。