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

总结 目前心力衰竭（HF）的治疗主要针对适应不良的心外神经激素回路 “一刀切”的方法。对于直接基于机制的治疗， 在HF的早期阶段靶向心脏。越来越多的证据表明， 心力衰竭时，线粒体产生ATP变得失调。一个公认的代谢特征， 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变为其他燃料， 葡萄糖。这种燃料转换发生在心脏肥大和衰竭的早期。但 这种心脏燃料转换与线粒体呼吸功能进行性减少的潜在联系， 在HF的发展过程中，ATP的产生能力还没有被确定为仅仅是一种联系。 在目前的资助期间，我们已经取得了一系列的发现，支持的前提是， 心脏脂肪酸氧化（FAO）的紊乱导致线粒体能量障碍， 发展HF包括：1）确定粮农组织途径最后步骤中的独特“瓶颈” 为辅酶A（CoA）等关键辅因子的消耗和还原当量的转移奠定基础 远离复合物I的电子传递链; 2）酮体，3-羟基丁酸酯（3OHB），一个有效的 心脏燃料，绕过长链粮农组织，减少心脏重塑和心室功能障碍，在小， HF的大型动物模型;和3）通过以下方式增加心脏线粒体氧化能力，包括FAO通量： 编码RIP 140（Nrip 1）的基因的心脏特异性缺失防止心脏肥大性生长并减少 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 这一多PI R 01更新提案的假设：FAO在肥大心脏中的下调导致 在β-氧化螺旋内的收缩导致线粒体ATP能力降低 减少粮农组织的通量为利用来自葡萄糖的碳源奠定了基础， 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 两个目标的考验。在目标1中，我们将对心脏功能、线粒体、 野生型、csRIP 140-/-（高FAO）和csPPAR 140-/-（低FAO）小鼠在 小鼠中HF的发展。目的2旨在确定RIP 140缺陷防御的机制 对抗病理性心脏肥大拟议工作的长期目标是确定 在衰竭的心脏中导致线粒体能量崩溃的机械事件，并确定节点 可以作为候选治疗策略的监管点，旨在重新平衡燃料利用率， 增强线粒体ATP产生能力，旨在心力衰竭的早期阶段。

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.