Creatine kinase–mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved
| Autor: | Jason Su, Viviane Caceres, Vadappuram P. Chacko, Ashwin Akki, Michelle K. Leppo, Gary Gerstenblith, Robert G. Weiss, D. Brian Foster, Yibin Wang, Ashish Gupta, Sa Shi, Nazareno Paolocci, Jonathan A. Kirk, Charles Steenbergen, Shenghan Lai |
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| Rok vydání: | 2012 |
| Předmět: |
medicine.medical_specialty
Gene Expression Mice Transgenic Adenosine Triphosphate Animals Creatine Kinase MM Form Disease Models Animal Dobutamine Energy Metabolism Heart Failure In Vitro Techniques Mice Mice Inbred C57BL Myocardial Contraction Perfusion Recombinant Proteins Inbred C57BL Transgenic chemistry.chemical_compound In vivo Internal medicine medicine Creatine Kinase MM Form biology Animal General Medicine medicine.disease Endocrinology chemistry Heart failure Disease Models biology.protein Creatine kinase Myofibril Adenosine triphosphate Ex vivo Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 122:291-302 |
| ISSN: | 0021-9738 |
| Popis: | ATP is required for normal cardiac contractile function, and it has long been hypothesized that reduced energy delivery contributes to the contractile dysfunction of heart failure (HF). Despite experimental and clinical HF data showing reduced metabolism through cardiac creatine kinase (CK), the major myocardial energy reserve and temporal ATP buffer, a causal relationship between reduced ATP-CK metabolism and contractile dysfunction in HF has never been demonstrated. Here, we generated mice conditionally overexpressing the myofibrillar isoform of CK (CK-M) to test the hypothesis that augmenting impaired CK-related energy metabolism improves contractile function in HF. CK-M overexpression significantly increased ATP flux through CK ex vivo and in vivo but did not alter contractile function in normal mice. It also led to significantly increased contractile function at baseline and during adrenergic stimulation and increased survival after thoracic aortic constriction (TAC) surgery-induced HF. Withdrawal of CK-M overexpression after TAC resulted in a significant decline in contractile function as compared with animals in which CK-M overexpression was maintained. These observations provide direct evidence that the failing heart is "energy starved" as it relates to CK. In addition, these data identify CK as a promising therapeutic target for preventing and treating HF and possibly diseases involving energy-dependent dysfunction in other organs with temporally varying energy demands. |
| Databáze: | OpenAIRE |
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