Advanced search
1 file | 644.03 KB

Decreased soluble guanylate cyclase contributes to cardiac dysfunction induced by chronic doxorubicin treatment in mice

(2017) ANTIOXIDANTS & REDOX SIGNALING. 26(4). p.153-164
Author
Organization
Abstract
Aims: 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. Results: 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 alpha 1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGC alpha 1 allele [sGC alpha 1(-/-CM)]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGC alpha 1(-/-CM) than 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 sGC alpha 1 mutant (DNsGC alpha 1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGC alpha 1(tg/+), but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGC alpha 1(tg/+) and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGC alpha 1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGC alpha 1-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.
Keywords
NITRIC-OXIDE, INDUCED CARDIOMYOPATHY, HEART-FAILURE, OXIDATIVE STRESS, RADICAL PRODUCTION, HYDROGEN-PEROXIDE, ACTIVATES SERCA, CARDIOTOXICITY, DEXRAZOXANE, ADRIAMYCIN, cardiovascular, cardiomyopathy, chemotherapy, doxorubicin, cyclic, nucleotides, soluble guanylate cyclase

Downloads

  • 2694 16Vandenwijngaert.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 644.03 KB

Citation

Please use this url to cite or link to this publication:

Chicago
Vandenwijngaert, Sara, Melissa Swinnen, Ann-Sophie Walravens, Manu Beerens, Hilde Gillijns, Ellen Caluwe, Robert E Tainsh, et al. 2017. “Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice.” Antioxidants & Redox Signaling 26 (4): 153–164.
APA
Vandenwijngaert, S., Swinnen, M., Walravens, A.-S., Beerens, M., Gillijns, H., Caluwe, E., Tainsh, R. E., et al. (2017). Decreased soluble guanylate cyclase contributes to cardiac dysfunction induced by chronic doxorubicin treatment in mice. ANTIOXIDANTS & REDOX SIGNALING, 26(4), 153–164.
Vancouver
1.
Vandenwijngaert S, Swinnen M, Walravens A-S, Beerens M, Gillijns H, Caluwe E, et al. Decreased soluble guanylate cyclase contributes to cardiac dysfunction induced by chronic doxorubicin treatment in mice. ANTIOXIDANTS & REDOX SIGNALING. 2017;26(4):153–64.
MLA
Vandenwijngaert, Sara, Melissa Swinnen, Ann-Sophie Walravens, et al. “Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice.” ANTIOXIDANTS & REDOX SIGNALING 26.4 (2017): 153–164. Print.
@article{8510066,
  abstract     = {Aims: 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. Results: 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 alpha 1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGC alpha 1 allele [sGC alpha 1(-/-CM)]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGC alpha 1(-/-CM) than 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 sGC alpha 1 mutant (DNsGC alpha 1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGC alpha 1(tg/+), but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGC alpha 1(tg/+) and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGC alpha 1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGC alpha 1-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.},
  author       = {Vandenwijngaert, Sara and Swinnen, Melissa and Walravens, Ann-Sophie and Beerens, Manu and Gillijns, Hilde and Caluwe, Ellen and Tainsh, Robert E and Nathan, Daniel I and Allen, Kaitlin and Brouckaert, Peter and Bartunek, Jozef and Scherrer-Crosbie, Marielle and Bloch, Kenneth D and Bloch, Donald B and Janssens, Stefan P and Buys, Emmanuel S},
  issn         = {1523-0864},
  journal      = {ANTIOXIDANTS \& REDOX SIGNALING},
  keyword      = {NITRIC-OXIDE,INDUCED CARDIOMYOPATHY,HEART-FAILURE,OXIDATIVE STRESS,RADICAL PRODUCTION,HYDROGEN-PEROXIDE,ACTIVATES SERCA,CARDIOTOXICITY,DEXRAZOXANE,ADRIAMYCIN,cardiovascular,cardiomyopathy,chemotherapy,doxorubicin,cyclic,nucleotides,soluble guanylate cyclase},
  language     = {eng},
  number       = {4},
  pages        = {153--164},
  title        = {Decreased soluble guanylate cyclase contributes to cardiac dysfunction induced by chronic doxorubicin treatment in mice},
  url          = {http://dx.doi.org/10.1089/ars.2015.6542},
  volume       = {26},
  year         = {2017},
}

Altmetric
View in Altmetric
Web of Science
Times cited: