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The metabolic modulators, Etomoxir and NVP-LAB121, fail to reverse pressure overload induced heart failure in vivo

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Abstract

Shifting substrate oxidation in heart muscle from fatty acids to glucose (substrate-switch) may improve contractile function in heart failure. We tested whether application of two agents (etomoxir and NVP-LAB121) capable of inducing a substrate-switch reverts the onset of heart failure in rats with chronic pressure-overload. Hypertrophy was induced by aortic banding in rats for 1 or 15 weeks. Rats were treated for 10 days with the CPT-1-inhibitor etomoxir [29.5 μmol/(kg day)] or with NVP-LAB121 [60 μmol/(kg day)], a pyruvate-dehydrogenase-kinase-inhibitor, before assessment by echocardiography and perfusion as isolated working hearts. We also analyzed PDH- and CPT1-activity and expression of α- and β-MHC by RT-PCR. Aortic banding increased heart-to-body-weight-ratio (g/kg) from 3.44 ± 0.26 to 4.14 ± 0.48 after 1 week and from 2.80 ± 0.21 to 6.54 ± 0.26 after 15 weeks. Ejection fraction was impaired after 15 weeks (57 ± 11 vs. 73 ± 8%, P < 0.05) and rats exhibited signs of heart failure. Total PDH activity was the same in all groups. CPT-1 activity was unchanged after 1 week but decreased after 15 weeks (P < 0.01). Neither etomoxir nor NVP-LAB121 affected cardiac function in vivo, but etomoxir improved function of the isolated heart. The drugs did not affect total PDH and CPT-1 activity, but increased PDH-activity status, prevented a decrease in PDK4 expression in heart failure, increased α and β-MHC expression and shifted substrate oxidation toward glucose in the isolated working rat heart. In conclusion, pharmacologic induction of substrate-switching is associated with changes in myofibrillar isoform expression but does not reverse heart failure in vivo. The improvement of function in vitro deserves further investigation.

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Acknowledgments

TD is Heisenberg-Professor of the Deutsche Forschungsgemeinschaft (DFG) at the University of Leipzig and the study was supported by DFG grants to TD (Do602/3-2, 4-1, 6-1, and 8-1). The authors thank Heinrich Taegtmeyer M.D., D.Phil. for advice. We thank Vitalij Maks for expert technical assistance.

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Authors and Affiliations

  1. Department of Cardiac Surgery, University of Leipzig Heart Center, Struempellstr. 39, 04289, Leipzig, Germany

    Michael Schwarzer, Gloria Faerber, Daniel Blum, Gracjan Pytel, Friedrich W. Mohr & Torsten Doenst

  2. Department of Cardiovascular Surgery, University of Freiburg, Freiburg, Germany

    Tilmann Rueckauer

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  1. Michael Schwarzer
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  2. Gloria Faerber
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  3. Tilmann Rueckauer
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  7. Torsten Doenst
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Correspondence to Torsten Doenst.

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Schwarzer, M., Faerber, G., Rueckauer, T. et al. The metabolic modulators, Etomoxir and NVP-LAB121, fail to reverse pressure overload induced heart failure in vivo. Basic Res Cardiol 104, 547–557 (2009). https://doi.org/10.1007/s00395-009-0015-5

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  • DOI: https://doi.org/10.1007/s00395-009-0015-5

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