title: Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice.
abstract: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity.
  
  
  
  Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC α1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGCα1 allele [sGCα1-/-CM]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGCα1-/-CMthan WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGCα1 mutant (DNsGCα1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGCα1tg/+, but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGCα1tg/+and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGCα1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGCα1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin-associated cardiotoxicity. Antioxid. Redox Signal. 26, 153-164.
authors: 1 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School , Anesthesia Center for Critical Care Research, Boston, Massachusetts.
authors: Sara
authors: S
authors: Vandenwijngaert
authors: 2 Department of Cardiovascular Sciences, KU Leuven , Leuven, Belgium .
authors: Melissa
authors: M
authors: Swinnen
authors: 2 Department of Cardiovascular Sciences, KU Leuven , Leuven, Belgium .
authors: Ann-Sophie
authors: AS
authors: Walravens
authors: 2 Department of Cardiovascular Sciences, KU Leuven , Leuven, Belgium .
authors: Manu
authors: M
authors: Beerens
authors: 2 Department of Cardiovascular Sciences, KU Leuven , Leuven, Belgium .
authors: Hilde
authors: H
authors: Gillijns
authors: 2 Department of Cardiovascular Sciences, KU Leuven , Leuven, Belgium .
authors: Ellen
authors: E
authors: Caluwé
authors: 1 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School , Anesthesia Center for Critical Care Research, Boston, Massachusetts.
authors: Robert E
authors: RE
authors: Tainsh
authors: 1 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School , Anesthesia Center for Critical Care Research, Boston, Massachusetts.
authors: Daniel I
authors: DI
authors: Nathan
authors: 1 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School , Anesthesia Center for Critical Care Research, Boston, Massachusetts.
authors: Kaitlin
authors: K
authors: Allen
authors: 3 Department of Biomedical Molecular Biology, Ghent University and Flanders Institute for Biotechnology , Ghent, Belgium .
authors: Peter
authors: P
authors: Brouckaert
authors: 2 Department of Cardiovascular Sciences, KU Leuven , Leuven, Belgium .|4 Cardiovascular Center , OLV Hospital, Aalst, Belgium .
authors: Jozef
authors: J
authors: Bartunek
authors: 5 Cardiovascular Research Center, Massachusetts General Hospital Research Institute and Harvard Medical School , Boston, Massachusetts.
authors: Marielle
authors: M
authors: Scherrer-Crosbie
authors: 1 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School , Anesthesia Center for Critical Care Research, Boston, Massachusetts.|5 Cardiovascular Research Center, Massachusetts General Hospital Research Institute and Harvard Medical School , Boston, Massachusetts.
authors: Kenneth D
authors: KD
authors: Bloch
authors: 1 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School , Anesthesia Center for Critical Care Research, Boston, Massachusetts.|6 Department of Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School , Boston, Massachusetts.
authors: Donald B
authors: DB
authors: Bloch
authors: 2 Department of Cardiovascular Sciences, KU Leuven , Leuven, Belgium .
authors: Stefan P
authors: SP
authors: Janssens
authors: 1 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School , Anesthesia Center for Critical Care Research, Boston, Massachusetts.
authors: Emmanuel S
authors: ES
authors: Buys
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D066126:Cardiotoxicity; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006331:Heart Diseases / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase / Q000097:blood* / Q000172:deficiency; D018754:Ventricular Dysfunction
chemical_list: D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D000071756:Soluble Guanylyl Cyclase
keywords: cardiomyopathy; cardiovascular; chemotherapy; cyclic nucleotides; doxorubicin; soluble guanylate cyclase