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Soluble guanylyl cyclase activation improves progressive cardiac remodeling and failure after myocardial infarction. Cardioprotection over ACE inhibition

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Abstract

Impaired nitric oxide (NO)–soluble guanylate cyclase (sGC)–cGMP signaling is involved in the pathogenesis of ischemic heart diseases, yet the impact of long-term sGC activation on progressive cardiac remodeling and heart failure after myocardial infarction (MI) has not been explored. Moreover, it is unknown whether stimulating the NO/heme-independent sGC provides additional benefits to ACE inhibition in chronic ischemic heart failure. Starting 10 days after MI, rats were treated with placebo, the sGC activator ataciguat (10 mg/kg/twice daily), ramipril (1 mg/kg/day), or a combination of both for 9 weeks. Long-term ataciguat therapy reduced left ventricular (LV) diastolic filling pressure and pulmonary edema, improved the rightward shift of the pressure–volume curve, LV contractile function and diastolic stiffness, without lowering blood pressure. NO/heme-independent sGC activation provided protection over ACE inhibition against mitochondrial superoxide production and progressive fibrotic remodeling, ultimately leading to a further improvement of cardiac performance, hypertrophic growth and heart failure. We found that ataciguat stimulating sGC activity was potentiated in (myo)fibroblasts during hypoxia-induced oxidative stress and that NO/heme-independent sGC activation modulated fibroblast–cardiomyocyte crosstalk in the context of heart failure and hypoxia. In addition, ataciguat inhibited human cardiac fibroblast differentiation and extracellular matrix protein production in response to TGF-β1. Overall, long-term sGC activation targeting extracellular matrix homeostasis conferred cardioprotection against progressive cardiac dysfunction, pathological remodeling and heart failure after myocardial infarction. NO/heme-independent sGC activation may prove to be a useful therapeutic target in patients with chronic heart failure and ongoing fibrotic remodeling.

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Acknowledgments

We thank Susanne Schraut, Martina Kasten and Silke Pretzer for expert technical assistance. This study was partly supported by a research grant from Sanofi-Aventis.

Conflict of interest

Daniela Fraccarollo and Johann Bauersachs received research grant support from Sanofi-Aventis related to ataciguat.

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Authors and Affiliations

  1. Klinik fuer Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30175, Hannover, Germany

    Daniela Fraccarollo, Paolo Galuppo, Andreas Schäfer & Johann Bauersachs

  2. Klinik und Poliklinik fuer Dermatologie, Venerologie und Allergologie, Universitätsklinikum Wuerzburg, Würzburg, Germany

    Stephanie Motschenbacher

  3. Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany

    Hartmut Ruetten

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  1. Daniela Fraccarollo
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  2. Paolo Galuppo
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  3. Stephanie Motschenbacher
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  4. Hartmut Ruetten
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  5. Andreas Schäfer
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  6. Johann Bauersachs
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Correspondence to Johann Bauersachs.

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Fraccarollo, D., Galuppo, P., Motschenbacher, S. et al. Soluble guanylyl cyclase activation improves progressive cardiac remodeling and failure after myocardial infarction. Cardioprotection over ACE inhibition. Basic Res Cardiol 109, 421 (2014). https://doi.org/10.1007/s00395-014-0421-1

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