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Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure

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Abstract

Background

Diastolic heart failure is a rising problem with a high incidence and similar mortality and morbidity compared to patients with systolic heart failure. Nevertheless, the underlying pathophysiology is still debated.

Aim

We investigated the effect of pharmacological enhancement of endothelial nitric oxide synthase (eNOS) on experimental diastolic heart failure (DHF).

Methods

DHF was induced in 60 DAHL salt-sensitive rats by salt diet in 8-week-old animals. 30 were treated with the eNOS enhancer AVE3085 (DHFeNOS) and 30 with placebo (DHF). Rats with normal salt intake served as controls.

Results and conclusion

Diastolic dysfunction with increased diastolic stiffness constant and increased left ventricular (LV) pressure was analyzed by invasive pressure–volume loop measurements in the DHF group compared to controls. Cardiac hypertrophy as indicated by LV mass measurements by echocardiography, and increased cardiac collagen content as measured by immunohistochemistry were associated with an increased activation state of calcineurin, AKT, ERK½, but not JNK and p38 kinases. Titin isoforms were not altered in this model of DHF. Treatment with AVE3085 significantly increased eNOS mRNA and protein levels in the cardiac tissue and decreases NAD(P)H oxidase subunits p22phox and gp91phox. Diastolic dysfunction was attenuated and cardiac hypertrophy and fibrosis were improved in comparison with untreated DHF animals. This was associated with a normalized activation state of calcineurin, AKT and ERK½. Therefore, we suggest that targeting the NO system might yield a future therapeutic aim for the treatment of DHF.

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Acknowledgments

The authors thank M. Kasner for final proof reading of the manuscript. This study was supported by the Deutsche Forschungsgemeinschaft (SFB-TR-19; A2, Z3).

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Authors and Affiliations

  1. Department of Cardiology and Pneumology, Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany

    Dirk Westermann, Alexander Riad, Utz Richter, Sebastian Jäger, Konstantinos Savvatis, Heinz-Peter Schultheiss & Carsten Tschöpe

  2. Department of Hematology, Charité, Universititätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

    Dirk Nagorsen

  3. Neuromuscular and Cardiovascular Cell Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

    Nora Bergmann & Michael Gotthardt

  4. Department of Nephrology, Charité, Universititätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

    Mirjam Schuchardt & Markus Tölle

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  1. Dirk Westermann
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  2. Alexander Riad
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  3. Utz Richter
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Correspondence to Carsten Tschöpe.

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Westermann, D., Riad, A., Richter, U. et al. Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure. Basic Res Cardiol 104, 499–509 (2009). https://doi.org/10.1007/s00395-009-0014-6

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  • DOI: https://doi.org/10.1007/s00395-009-0014-6

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