ATPIF1作为靶标治疗压力超负荷心脏肥厚和心力衰竭的效果与机制

Cardiac hypertrophy is a major risk factor in the development of congestive heart failure. Mitochondrial dysfunction is a hallmark of numerous human diseases, including pathological cardiac hypertrophy and heart failure, which is the main cause of mortality. ATP synthase is an enzyme that catalyzes the final coupling step of oxidative energy production. It is well established that myocardial ATP depletion is a key feature of heart failure. Because the mitochondrial ATP synthase has a key role in energy production and is highly regulated in response to cellular energy needs, it should be a key site for regulation of mitochondrial respiration. ATPIF1 is a natural ATP synthase inhibitor protein that regulates ATP synthase in metabolically active cells. However, its role in the energy demanding heart remains obscured. Preliminary studies demonstrated that ATPIF1 was upregulated in failing hearts. Mice with ATPIF1 knockout were protected against isoproterenol induced cardiac dysfunction. Therefore, we hypothesized that ATPIF1 plays a crucial role in the maladaptive responses of the heart under stress conditions. The loss of ATPIF1 could protect the heart against the progression from cardiac hypertrophy to heart failure under pressure overload condition via enhancing mitochondrial function. This project will utilize animal models with ATPIF1knockout and conditional transgenic overexpression to unravel the molecular and biochemical mechanisms underlying ATPIF1’s role in the pathologic heart, providing new insights for the development of a novel therapeutic target of treating heart failure.

心脏肥厚是充血性心脏衰竭的主要危险因素，在心脏肥厚到心衰的发生发展过程中，线粒体功能紊乱和能量代谢失调起着重要的作用。ATP合成酶是生物体中能量转换的关键酶，主宰氧化磷酸化与ATP生成和水解，对线粒体功能和能量代谢起着至关重要的作用。已有研究表明ATPIF1在线粒体功能和能量代谢的调控中起着重要的作用，但它在心脏病生理上的作用仍不清楚。预实验发现, 晚期心衰病人和心脏肥厚动物心肌ATPIF1表达均显著升高；ATPIF1敲除小鼠能减少异丙肾上腺诱导的心脏损伤。本课题组据此提出科学假设：在心脏肥厚及心衰过程中出现的心脏ATPIF1高表达破坏线粒体功能和增加细胞凋亡，从而加速心衰的进程，阻断ATPIF1可以防止心肌肥厚向心衰的发展。本课题将利用转基因高表达和基因敲除动物模型为研究手段，解析针对ATPIF1防治心肌肥厚发展到心衰的分子机制，为临床以ATPIF1为新靶点治疗心衰提供科学依据和新思路。

线粒体ATP合酶催化线粒体氧化磷酸化的偶联功能。在病理条件下，ATP合酶水解ATP以将质子从基质回到膜间腔，从而维持线粒体膜电位。 ATP合酶抑制因子1（ATPIF1）是一种核编码的ATP合酶相互作用蛋白，可选择性抑制ATP合酶的水解活性，这可能在缺血性心脏中发挥ATPIF1的保护作用。但是，ATPIF1的体内心脏功能和靶向ATPIF1的潜在治疗应用仍然不清楚。在本研究中，我们发现在压力超负荷引起的肥大的小鼠心脏和扩张型心肌病的人心脏中，ATPIF1上调。ATPIF1基因敲除（KO）小鼠可防止心脏功能障碍和主动脉缩窄（TAC）或异丙肾上腺素引起的病理发展。降低ATP水解激活了ATPIF1 KO心脏中的AMPK活性，共同促进了细胞自噬。这些结果表明，心脏衰竭中的ATPIF1上调可能是适应不良的反应。在肥大心脏中抑制ATPIF1不仅可以防止细胞因线粒体去极化过度而死亡，还可以激活AMPK信号并增加细胞自噬。因此，ATPIF1抑制可作为潜在的治疗靶点，治疗病理性心脏肥大和心力衰竭。

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