Probing the Role of Mitochondrial Short-chain Carbon Homeostasis in the Hypertrophied and Failing Heart

摘要 目前心力衰竭(HF)的治疗主要针对不适应的心外神经激素回路。 在“一刀切”的方法下。对直接基于机制的治疗有重大的未得到满足的需求 在心力衰竭早期以心脏为靶点。越来越多的证据表明，在疾病的发展过程中 心力衰竭，线粒体产生的三磷酸腺苷变得失调。一个公认的新陈代谢特征 衰竭的心脏是从使用脂肪酸作为正常心脏的主要燃料来源，转向使用其他燃料 作为葡萄糖。这种能量转换发生在心肌肥大和衰竭的早期。然而， 这种心脏燃料转换与线粒体呼吸功能进行性下降和 在HF的发展过程中，ATP的生产能力并不仅仅是一种联系。 在当前的资助期内，我们取得了一系列发现，这些发现支持这样一个前提 心肌脂肪酸氧化(FAO)紊乱导致线粒体能量功能障碍 HF的发展包括：1)查明粮农组织途径末端步骤中的明显“瓶颈” 为辅酶A(CoA)等关键辅因子的枯竭和还原等价物的转移奠定基础 远离电子传输链的络合物I；2)酮体，3-羟基丁酸酯(3OHB)，有效的 绕过长链FAO的心脏燃料，减少小鼠和小鼠心脏重构和心功能障碍 3)增加心肌线粒体的氧化能力，包括粮农组织的流量，通过 心脏特异缺失编码RIP140(Nrig1)的基因可防止心肌肥大生长并减少 压力超负荷引起的小鼠心脏重构和功能障碍。这些发现导致了中央 多PI R01更新方案的假设：在肥厚的心脏结果中下调FAO的表达 氧化螺旋内的瓶颈导致线粒体ATP能力降低 产量和；粮农组织通量的减少为利用葡萄糖和 心脏肥大生长所必需的合成代谢途径中的其他来源。这些假设将是 经过两个目标的检验。在目标1中，我们将对心脏功能、线粒体、 野生型csRIP140-/-(高粮农组织)和csPPAR-/-(低粮农组织)小鼠在 心衰在小鼠体内的发育。目标2旨在确定RIP140缺陷的防御机制 抗病理性心肌肥大生长。拟议工作的长期目标是确定 导致衰竭心脏线粒体能量崩溃和识别结节的机械性事件 可作为候选治疗策略的监管要点，旨在重新平衡燃料利用和 针对心力衰竭的早期阶段，增强线粒体ATP的产生能力。

SUMMARY Current therapies for heart failure (HF) are largely directed at maladaptive extra-cardiac neurohormonal circuits in a “one size fits all” approach. There is a significant unmet need for mechanism-based therapies directly targeting the heart during early stages of HF. Increasing evidence has shown that during the development of heart failure, mitochondrial generation of ATP becomes dysregulated. A well-established metabolic signature of the failing heart is a shift from using fatty acids as the chief fuel source of the normal heart, to other fuels such as glucose. This fuel shift occurs early in the development of cardiac hypertrophy and failure. However, the potential linkage of this cardiac fuel switch to the progressive diminution in mitochondrial respiratory function and ATP producing capacity during the development of HF has not been established beyond a mere association. During the current funding period, we have made a series of discoveries that support the premise that disturbances in cardiac fatty acid oxidation (FAO) contribute to mitochondrial energetic dysfunction and the development of HF including: 1) identification of distinct “bottlenecks” in the terminal steps of the FAO pathway setting the stage for depletion of key cofactors such as Coenzyme A (CoA) and diversion of reducing equivalents away from complex I of the electron transport chain; 2) the ketone body, 3-hydroxybutryate (3OHB), an efficient cardiac fuel that bypasses long-chain FAO, reduces cardiac remodeling and ventricular dysfunction in small and large animal models of HF; and 3) increasing cardiac mitochondrial oxidative capacity, including FAO flux, by cardiac-specific deletion of the gene encoding RIP140 (Nrip1) prevents cardiac hypertrophic growth and reduces cardiac remodeling and dysfunction caused by pressure overload in mice. These findings have led to the central hypotheses of this multi-PI R01 renewal proposal: Downregulation of FAO in the hypertrophied heart results in bottlenecking within the -oxidation spiral leading to reduced capacity for mitochondrial ATP production and; reduced FAO flux sets the stage for utilization of carbon sources from glucose and other sources in anabolic pathways necessary for cardiac hypertrophic growth. These hypotheses will be tested by two aims. In Aim 1, we will conduct in-depth assessment of the cardiac functional, mitochondrial, proteomic and genomic response of wild-type, csRIP140-/- (high FAO), and csPPAR-/- (low FAO) mice during development of HF in mice. Aim 2 is designed to determine the mechanisms whereby RIP140 deficiency defends against pathological cardiac hypertrophic growth. The long-term objectives of the proposed work are to define the mechanistic events leading to mitochondrial energetic collapse in the failing heart and to identify nodal regulatory points that could serve as candidate therapeutic strategies aimed at re-balancing fuel utilization and enhancing mitochondrial ATP-producing capacity aimed at the early stages of heart failure.