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

  • Daniela Fraccarollo
  • Paolo Galuppo
  • Stephanie Motschenbacher
  • Hartmut Ruetten
  • Andreas Schäfer
  • Johann Bauersachs
Original Contribution

DOI: 10.1007/s00395-014-0421-1

Cite this article as:
Fraccarollo, D., Galuppo, P., Motschenbacher, S. et al. Basic Res Cardiol (2014) 109: 421. doi:10.1007/s00395-014-0421-1

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.

Keywords

Soluble guanylyl cyclase Myocardial infarction Heart failure Remodeling 

Supplementary material

395_2014_421_MOESM1_ESM.pdf (1 mb)
Supplementary material 1 (PDF 1034 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Daniela Fraccarollo
    • 1
  • Paolo Galuppo
    • 1
  • Stephanie Motschenbacher
    • 2
  • Hartmut Ruetten
    • 3
  • Andreas Schäfer
    • 1
  • Johann Bauersachs
    • 1
  1. 1.Klinik fuer Kardiologie und AngiologieMedizinische Hochschule HannoverHannoverGermany
  2. 2.Klinik und Poliklinik fuer Dermatologie, Venerologie und AllergologieUniversitätsklinikum WuerzburgWürzburgGermany
  3. 3.Sanofi-Aventis Deutschland GmbHFrankfurt am MainGermany

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