Abstract 515: Expression of Leptin, Adiponectin, and Activation of AMP Kinase in Failing and Mechanically Unloaded Human Hearts
| Autor: | Kenneth McGaffin, Benjamin Burkhead, Gregory Gibson, Christine Moravec, Charles McTiernan |
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| Rok vydání: | 2007 |
| Předmět: | |
| Zdroj: | Circulation. 116 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Introduction: The failing heart displays contractile dysfunction, increased workload and energy demands, and a switch in substrate utilization for ATP production from free fatty acid to glucose oxidation. ATP production is regulated by AMP Kinase (AMPK). In skeletal muscle, the cytokines leptin (OB) and adiponectin (AD) stimulate AMPK activity and result in preferential glucose metabolism. Both OB and AD are elevated in human heart failure (HF), but it is unknown whether these cytokines may alter AMPK activation in the failing and/or mechanically unloaded heart. Hypothesis : In human HF, elevated OB and AD levels: 1) are in part due to increased production by the cardiomyocyte; 2) are associated with cardiac AMPK activation; and 3) are downregulated under conditions of reduced workload and ATP requirement such as occurs with mechanical unloading. Methods/Results: Left ventricular tissue was obtained from 5 non-failing (NF), 10 end stage failing (F), and 8 paired pre/post ventricular assist device (VAD) patients. Results reported are fold change ± SEM relative to NF or pre VAD, compared by t-test . Relative to NF, F hearts showed (Real-time PCR) increased mRNA for BNP (4.4±0.4, P =0.04), OB (5.4±0.3, P =0.03), OBR (7.3±0.2, P =0.01) and AD (9.1±0.9, P =0.01), while levels of an unrelated gene, the grehlin receptor, were decreased (0.10±0.01, P =0.01). Immunoblotting confirmed similar changes in OB, OBR and AD protein levels, and immunoflurescence localized these proteins to the cardiomyocyte. Increased activation of AMPKα was observed in F hearts (1.9±0.2 fold increase vs NF, P =0.02) as assessed by the ratio of phosphorylated to total AMPKα. In paired pre and post VAD supported hearts, these changes were reversed after mechanical unloading as decreased BNP (0.020±0.001, P =0.01), OB (0.030±0.001, P =0.03), OBR (0.25±0.01, P =0.02) and AD (0.22±0.01, P =0.04) mRNAs were seen relative to the pre VAD state, whereas increased grehlin receptor mRNA was observed (7.6±0.5, P P =0.04) decrease in the activation of AMPK. Conclusions: OB and AD are produced by failing cardiomyocytes and may contribute to preferential use of glucose for energy production in HF through activation of AMPK. |
| Databáze: | OpenAIRE |
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