Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.
Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.
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DOI：
10.1161/circresaha.121.319648
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发表时间：
2022-03-04
影响因子：
20.1
通讯作者：
Weiss RG
中科院分区：
文献类型：
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作者：
Keceli G;Gupta A;Sourdon J;Gabr R;Schär M;Dey S;Tocchetti CG;Stuber A;Agrimi J;Zhang Y;Leppo M;Steenbergen C;Lai S;Yanek LR;O'Rourke B;Gerstenblith G;Bottomley PA;Wang Y;Paolocci N;Weiss RG
心脏能量代谢异常发生在心力衰竭（HF）中，并导致收缩功能障碍，但它们在HF相关的病理重塑中的作用（如果有的话）尚不明确。肌酸激酶（CK）是主要的肌肉能量储备反应，在肌原纤维处快速提供ATP并再生线粒体ADP，在实验和人HF中下调。验证人类心衰病理性重构与心肌CK能量代谢受损有关的假设，以及挽救CK可减轻实验性心衰的非适应性肥厚。首先，在27名HF患者和14名健康受试者中，我们分别使用无创磁共振31P谱和MRI测量了心脏能量学和左心室重构。其次，我们测试了心肌纤维CK （CKmyofib）或线粒体CK （CKmito）的心脏特异性过表达对小鼠hf相关的适应性不良肥厚的代谢拯救的影响。在人类中，病理性左室肥大和扩张与心肌ATP水平降低和通过CK合成ATP的速率密切相关。在小鼠中，横断主动脉收缩（TAC）引起的左室肥大和扩张可以通过过表达CKmito而不是过表达CKmyofib来减轻。CKmito过表达也能减轻慢性异丙肾上腺素刺激后的肥大。CKmito降低线粒体ROS和组织ROS水平，上调抗氧化剂及其启动子。当CKmito过表达小鼠的CK能力受到肌酸底物消耗的限制时，对病理性重构的保护作用就丧失了，这表明CKmito反应的ADP再生能力而不是CK蛋白本身对限制不良HF重构至关重要。在衰竭的人类心脏中，病理性肥大和不良重构与ATP水平和CK能量储备反应的缺陷密切相关。CKmito位于心脏能量学和氧化还原平衡的交叉点，在减轻心衰的病理性重塑中起着至关重要的作用。NCT00181259
Abnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. Creatine kinase (CK), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. To test the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF. First, in twenty-seven HF patients and fourteen healthy subjects, we measured cardiac energetics and left ventricular (LV) remodeling using noninvasive magnetic resonance 31P spectroscopy and MRI, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either myofibrillar CK (CKmyofib) or mitochondrial CK (CKmito) on HF-related maladaptive hypertrophy in mice. In people, pathologic LV hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction (TAC)-induced LV hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial ROS, tissue ROS levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling. In the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF. NCT00181259