Fatty acid oxidation suppresses cardiac hypertrophy

脂肪酸氧化抑制心脏肥大

• 批准号: 9100917
• 负责人: Rong Tian
• 金额: $ 68.97万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100917
• 关键词: ATP Synthesis Pathway; Acetyl-CoA Carboxylase; Address; Adult; Affect; Angiotensin II; Animal Model; Birth; Cardiac; Cardiac Myocytes; Carnitine O-Palmitoyltransferase; Cell Death; Cell Respiration; Ceramides; Chronic; Chronic stress; Data; Development; Diet; Diglycerides; Disease; Energy Metabolism; Energy Supply; Fatty Acids; Figs - dietary; Glucose; Goals; Growth; Health; Heart; Heart Hypertrophy; Heart failure; Hypertrophy; Lipids; Malonyl Coenzyme A; Metabolic; Mitochondria; Modeling; Mus; Myocardial; Myocardial dysfunction; Obesity; Oxidative Stress; Production; Research; SLC2A1 gene; Stable Isotope Labeling; Stimulus; Stress; Techniques; Testing; Time; Triglycerides; cell growth; fatty acid oxidation; glucose uptake; improved; inhibitor/antagonist; long chain fatty acid; metabolic profile; mitochondrial dysfunction; mouse model; overexpression; oxidation; preference; pressure; prevent; response; uptake

 DESCRIPTION (provided by applicant): It is widely recognized that pathological hypertrophy of the heart is associated with decreased fatty acid oxidation (FAO) and increased reliance on glucose utilization. Intensive research in the past decade has investigated whether the shift of substrate preference towards glucose is adaptive or maladaptive for the high energy demand of the heart. Evidence from these studies suggest that sustaining a high capacity for ATP synthesis via oxidative metabolism rather than the selection of substrates is critical for maintaining the energy supply to the heart during chronic stress. Prior studies by us and others have shown that increasing the oxidation of either glucose or fatty acids improves myocardial energetics and systolic function in chronically stress hearts. We thus ask whether decreased FAO affects mechanisms of heart failure beyond that for ATP production. It has been shown that decreased fatty acid oxidation in pathological hypertrophy is associated with decreased endogenous triglyceride turnover and accumulation of diglyceride and ceramide; in obesity animal models, cell death and pathological hypertrophy are also attributed to a mismatch of fatty acids uptake and oxidation which results in mitochondrial dysfunction, increased ROS and ER stress. In a recent study we sought to increase FAO by targeting the entry of long-chain fatty acids into the mitochondria via mCPT-1, the rate-limiting step. This was achieved by the deletion of acetyl-CoA carboxylase 2 (ACC2) which catalyze the formation of malonyl-CoA, an inhibitor of mCPT-1. Cardiac-specific deletion of ACC2 in mice (cKO) resulted in a 50% increase of FAO without affecting survival or cardiac function in the long term. Furthermore, it maintained normal metabolic profile and protected against the development of pathological hypertrophy and cardiac dysfunction during chronic pressure overload (TAC). Notably, the benefit in cKO is not limited to improved ATP supply from FAO as the cKO markedly decreased cardiac hypertrophy after TAC while increasing glucose uptake and utilization by overexpressing GLUT1 improved cardiac energetics and function but did not reduce hypertrophy. These observations have led us to hypothesize that sustaining fatty acid oxidation in the heart protects against the development of pathological hypertrophy during chronic stress. To address the question whether the above observations were due to the adaptive responses triggered by the deficiency of ACC2 at birth in the cKO we developed a mouse model with inducible deletion of ACC2 (iKO) in the heart. This model will also allow us to determine whether increasing FAO can arrest or regress existing pathological hypertrophy. Our preliminary data show that deletion of ACC2 in the adult mouse heart results in a similar increase of FAO as observed in cKO, and it suppressed the development of pathological hypertrophy by either angiotensin II (AngII) or diet-induced obesity. Therefore, our goal in the proposed studies are 1) to determine the mechanisms by which sustaining myocardial FAO protects against cardiac hypertrophy; 2) to test whether upregulating FAO can reverse the pathological remodeling and failure of the heart.

 描述（由申请人提供）：人们普遍认为，心脏病理性肥大与脂肪酸氧化（FAO）减少和对葡萄糖利用的依赖性增加有关。过去十年的深入研究已经调查了底物偏好向葡萄糖的转变对于心脏的高能量需求是适应性的还是不适应的。这些研究的证据表明，通过氧化代谢而不是选择底物来维持ATP合成的高能力对于在慢性应激期间维持心脏的能量供应至关重要。我们和其他人先前的研究表明，增加葡萄糖或脂肪酸的氧化可以改善慢性应激心脏的心肌能量和收缩功能。因此，我们要问的是，FAO减少是否会影响心力衰竭的机制，而不仅仅是ATP的产生。已经表明，病理性肥大中脂肪酸氧化减少与内源性甘油三酯周转减少以及甘油二酯和神经酰胺的积累有关;在肥胖动物模型中，细胞死亡和病理性肥大也归因于脂肪酸摄取和氧化的不匹配，这导致线粒体功能障碍、ROS和ER应激增加。在最近的一项研究中，我们试图通过靶向长链脂肪酸通过mCPT-1（限速步骤）进入线粒体来增加FAO。这是通过删除乙酰辅酶A羧化酶2（ACC 2）来实现的，ACC 2催化丙二酰辅酶A（mCPT-1的抑制剂）的形成。心脏特异性缺失小鼠ACC 2（cKO）导致FAO增加50%，而不会影响长期存活或心脏功能。此外，在慢性压力超负荷（TAC）期间，它维持正常的代谢特征并防止病理性肥大和心功能不全的发展。值得注意的是，cKO的益处不限于改善FAO的ATP供应，因为cKO显著降低了TAC后的心脏肥大，同时通过过表达GLUT 1增加葡萄糖摄取和利用，改善了心脏能量和功能，但没有减少肥大。这些观察结果使我们假设，在慢性应激期间，心脏中持续的脂肪酸氧化可以防止病理性肥大的发展。为了解决上述观察结果是否是由于cKO中出生时ACC 2缺陷引发的适应性反应的问题，我们开发了心脏中具有ACC 2诱导性缺失（iKO）的小鼠模型。该模型还将使我们能够确定增加FAO是否可以阻止或逆转现有的病理性肥大。我们的初步数据表明，ACC 2在成年小鼠心脏中的缺失导致与在cKO中观察到的类似的FAO增加，并且它抑制了由血管紧张素II（AngII）或饮食诱导的肥胖引起的病理性肥大的发展。因此，我们在拟议研究中的目标是：1）确定维持心肌FAO保护心脏肥大的机制; 2）测试上调FAO是否可以逆转心脏的病理性重塑和衰竭。