title: Soluble guanylyl cyclase activation improves progressive cardiac remodeling and failure after myocardial infarction. Cardioprotection over ACE inhibition.
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.
authors.affiliation: Klinik fuer Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30175, Hannover, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraccarollo
authors.forename: Paolo
authors.initials: P
authors.lastname: Galuppo
authors.forename: Stephanie
authors.initials: S
authors.lastname: Motschenbacher
authors.forename: Hartmut
authors.initials: H
authors.lastname: Ruetten
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäfer
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002450:Cell Communication; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D006162:Guanylate Cyclase / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017257:Ramipril / Q000494:pharmacology*; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013449:Sulfonamides / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002316:Cardiotonic Agents; D020536:Enzyme Activators; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D062367:ortho-Aminobenzoates; D013481:Superoxides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D017257:Ramipril; C515616:5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide