Fatty acid oxidation suppresses cardiac hypertrophy

 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减少(FAO)和对葡萄糖利用的依赖增加有关。在过去的十年里，密集的研究已经调查了底物偏好向葡萄糖的转变是适应还是不适应心脏的高能量需求。这些研究的证据表明，在慢性应激期间，通过氧化代谢而不是底物的选择来维持高的ATP合成能力是维持心脏能量供应的关键。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，我们问粮农组织的减少是否影响了心力衰竭的机制，而不是影响ATP的产生。已有研究表明，病理性肥厚时脂肪酸氧化减少与内源性甘油三酯周转减少、甘油三酯和神经酰胺蓄积有关；在肥胖动物模型中，细胞死亡和病理性肥厚也归因于脂肪酸摄取和氧化不匹配，从而导致线粒体功能障碍、ROS增加和内质网应激。在最近的一项研究中，我们试图通过mCPT-1这一限速步骤，将长链脂肪酸进入线粒体作为目标，以增加粮农组织的产量。这是通过缺失乙酰辅酶A羧基酶2(ACC2)实现的，该酶催化形成mCPT-1的抑制剂丙二酰辅酶A。小鼠心脏特异的ACC2缺失(CKO)导致粮农组织增加50%，而不影响长期存活或心功能。此外，它还保持了正常的代谢特征，并防止慢性压力超负荷(TAC)期间发生病理性肥厚和心功能不全。值得注意的是，CKO的好处不仅限于粮农组织改善了ATP供应，因为CKO显著减少了TAC后的心肌肥厚，同时通过过表达GLUT1增加了葡萄糖的摄取和利用，改善了心脏的能量和功能，但没有减少肥厚。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厚的发展。为了解决上述观察结果是否源于CKO中出生时ACC2缺陷所引发的适应性反应的问题，我们建立了一种心脏ACC2(Iko)可诱导缺失的小鼠模型。这一模型还将使我们能够确定增加粮农组织是否可以阻止或消退现有的病理性肥大。我们的初步数据显示，在成年小鼠心脏中，ACC2的缺失导致了与在CKO中观察到的类似的FAO的增加，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厚的发展。因此，我们在拟议的研究中的目标是：1)确定维持心肌FAO保护心肌肥厚的机制；2)测试上调FAO是否可以逆转心脏的病理性重构和衰竭。

 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.