Adipose tissue ATGL regulates cardiac energy metabolism in heart failure

脂肪组织 ATGL 调节心力衰竭中的心脏能量代谢

• 批准号: 431080330
• 负责人: Professor Dr. Ulrich Kintscher
• 金额: --
• 依托单位: Center for Cardiovascular Research (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/431080330?language=en
• 关键词: Adipose; tissue; ATGL; regulates; cardiac

The development of chronic heart failure is characterized by a persistent over-activation of the sympathetic nervous system resulting in the well described cardiovascular consequences. In parallel, frequent adrenergic stimulation exerts crucial effects on adipose tissue metabolism, including a marked induction of adipose tissue lipolysis. We could recently show that adipose tissue lipolysis mediated by the adipose triglyceride lipase (ATGL) directly affectscardiac function during heart failure development involving fatty acid secretion from adipose tissue and changes of circulating lipids. The inhibition of adipose tissue ATGL activity resulted in an improvement of left ventricular function, and may serve as a new therapeutic target. But, the underlying molecular mechanisms by which adipose tissue ATGL regulates cardiac function are incompletely understood. Based on previous data this project aims to investigate the following mechanisms by which adipose tissue ATGL controls cardiac function in heart failure: (1) changes in cardiac energy substrate and systemic metabolism, (2) cardiac phospholipidome changes and the impact on cardiac mitochondrial function, and (3) regulation of cardiac inflammation and its link to mitochondrial function. To achieve these aims we will studyinducible adipose tissue-specific ATGL-deficient (Atgl-fl/fl-Adipoq-cre/ERT2) mice subjected to two different models of heart failure: transverse aortic constriction and prolonged stimulation with the betaadrenergic agonist isoproterenol. Mice will undergo comprehensivecardiac phenotyping including speckle-tracking echocardiography. To assess (1) cardiac energy metabolism we will perform cardiac PET analysis as well as MS-based metabolomics and lipidomics Analysis from left ventricular tissue samples. To determine (2) the relevance of cardiac mitochondrial function for adipose tissue ATGL´s cardioprotective actions, mitochondrial lipid composition and function will be investigated by MS-based mitochondrial lipidomics in isolatedmitochondria and analysis of mitochondrial respiration using the Seahorse technology in isolated primary cardiomyocytes from our models. Finally, our preliminary data points towards a (3) modification of cardiac inflammatory cell infiltration through adipose tissue ATGL.To further clarify this process we will perform an immune cell phenotyping by flow cytometry analysis of cardiac single cell suspensions in the above mentioned models. Finally, we will link the cardiac inflammatory response to mitochondrial dysfunction by investigating the accumulation of mitochondrial DNA in autolysosomes, and a subsequent activation of TLR-9 signaling in cardiomyocytes. In summary, the present study aims to exactly determine the underlying mechanisms of the cardioprotective Actions of adipose tissue ATGL-inhibition in chronic heart failure. These data will help to develop a new ATGL-based pharmacological approach for the treatment of chronic heart failure.

慢性心力衰竭的发展的特征是交感神经系统的持续过度激活导致心血管后果。同时，经常的肾上腺素模拟对脂肪组织代谢产生至关重要的影响，包括明显诱导脂肪组织脂肪分解。我们最近可以表明，脂肪组织脂解介导的脂肪甘油三酸酯脂肪酶（ATGL）在心力衰竭发育过程中直接影响促销性脂肪功能涉及脂肪组织的脂肪酸分泌和循环脂质的变化。脂肪组织ATGL活性的抑制作用导致左心室功能的改善，并且可以作为新的治疗靶点。但是，脂肪组织ATGL调节心脏功能的潜在分子机制是不完全理解的。基于先前的数据，该项目旨在研究脂肪组织ATGL控制心力衰竭中心脏功能的以下机制：（1）心脏能量底物和全身代谢的变化，（2）心脏磷脂的变化以及对心脏线粒体功能的影响，以及（3）（3）（3）（3）调节心脏感染与其链接对肌核的链接功能。为了实现这些目标，我们将研究可诱导的脂肪组织特异性ATGL缺陷型（ATGL/FL-FL/FL-ADIPOQ-CRE/ERT2）小鼠，受到了两种不同的心脏衰竭模型，横向主动脉衰竭：横向主动脉肿瘤延长刺激，并长时间刺激了βadrenrennecrennecren肾上腺素能的同倍醇。小鼠将进行全面的心脏表型，包括斑点跟踪超声心动图。为了评估（1）心脏能量代谢，我们将对左心室组织样品进行心脏宠物分析以及基于MS的代谢组学和脂质组学分析。为了确定（2）心脏线粒体功能与脂肪组织ATGL的心脏保护作用的相关性，使用MS基于MS的线粒体脂质组成和功能将在分离的线粒体呼吸中使用隔离的SeaHorse技术在我们的模型中使用隔离的线粒体呼吸技术进行研究。最后，我们的初步数据表明，通过脂肪组织ATGL对心脏炎症细胞浸润的修饰。为了进一步阐明这一过程，我们将通过上述模型中心脏单细胞悬浮液的流式细胞仪分析进行免疫细胞表型。最后，我们将通过研究线粒体DNA在自溶解体中的积累以及随后在心肌细胞中TLR-9信号传导的激活，将心脏炎症反应与线粒体功能障碍联系起来。总而言之，本研究旨在准确确定脂肪组织ATGL抑制在慢性心力衰竭中的心脏塑性作用的潜在机制。这些数据将有助于开发一种新的基于ATGL的药物方法来治疗慢性心力衰竭。