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

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

Basic research in cardiology (2014-06-09)
Daniela Fraccarollo, Paolo Galuppo, Stephanie Motschenbacher, Hartmut Ruetten, Andreas Schäfer, Johann Bauersachs
RESUMEN

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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HEPES, ≥99.5% (titration)
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DAPI, for nucleic acid staining
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HEPES, BioPerformance Certified, ≥99.5% (titration), suitable for cell culture
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HEPES buffer solution, 1 M in H2O
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HEPES, PharmaGrade, Manufactured under appropriate controls for use as a raw material in pharma or biopharmaceutical production, suitable for cell culture
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HEPES, BioUltra, for molecular biology, ≥99.5% (T)
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HEPES, BioXtra, pH 5.0-6.5 (1 M in H2O), ≥99.5% (titration)
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HEPES, BioXtra, suitable for mouse embryo cell culture, ≥99.5% (titration)
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HEPES, Pharmaceutical Secondary Standard; Certified Reference Material
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HEPES, anhydrous, free-flowing, Redi-Dri, ≥99.5%
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Ataciguat, ≥98% (HPLC)
SAFC
HEPES, PharmaGrade, Manufactured under appropriate controls for use as a raw material in pharma or biopharmaceutical production, suitable for cell culture

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