Fatty acid oxidation suppresses cardiac hypertrophy

脂肪酸氧化抑制心脏肥大

基本信息

批准号：
8977407
负责人：
Rong Tian
金额：
$ 68.64万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/8977407
关键词：
1,2-diacylglycerol 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 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 mitochondrial dysfunction mouse model overexpression oxidation preference pressure prevent public health relevance response uptake

项目摘要

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，心脏的病理性肥大与脂肪酸氧化（FAO）减少和对葡萄糖利用的依赖增加有关。过去十年的深入研究调查了底物偏好是否转向葡萄糖。这些研究的证据表明，通过氧化代谢而不是底物的选择来维持 ATP 合成的高能力对于维持心脏的能量供应至关重要。我们和其他人之前的研究表明，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，因此我们想知道，FAO 的减少是否会影响心力衰竭的机制，而不仅仅是影响 ATP 的产生。研究表明，病理性肥大中脂肪酸氧化的减少与肥胖动物模型中内源性甘油三酯周转率的降低以及甘油二酯和神经酰胺的积累、细胞死亡和病理性肥大有关。肥大还归因于脂肪酸摄取和氧化的不匹配，从而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 mCPT- 靶向长链脂肪酸进入线粒体来增加 FFA。 1，限速步骤，这是通过删除乙酰辅酶A羧化酶2（ACC2）来实现的，该酶催化丙二酰辅酶A的形成，丙二酰辅酶A是丙二酰辅酶A的抑制剂。 mCPT-1。小鼠心脏特异性删除 ACC2（cKO）可导致 FFA 增加 50%，而不会长期影响生存或心脏功能。此外，它还能维持正常的代谢特征，并防止发生病理性肥大。慢性压力超负荷 (TAC) 期间的心脏功能障碍值得注意的是，cKO 的益处不仅限于改善 FAO 的 ATP 供应，因为 cKO 显着减少了 TAC 后的心脏肥大，同时通过过度表达增加了葡萄糖的摄取和利用。 GLUT1 改善了心脏能量和功能，但没有减少肥厚。这些观察结果使我们认识到，心脏中持续的脂肪酸氧化可以防止慢性应激期间发生病理性肥大。出生时 cKO 中 ACC2 缺陷引发的适应性反应，我们开发了一种心脏中可诱导缺失 ACC2 (iKO) 的小鼠模型，该模型还将使我们能够确定增加FAO是否可以阻止或抑制。我们的初步数据表明，成年小鼠心脏中 ACC2 的缺失导致了与 cKO 中观察到的类似的 FAO 增加，并且它抑制了血管紧张素 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 预防心脏肥大的机制；2) 测试上调FAO 是否可以逆转病理。心脏的重塑和衰竭。