Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice.

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 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-/-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 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: Sara Vandenwijngaert, Melissa Swinnen, Ann-Sophie Walravens, Manu Beerens, Hilde Gillijns, Ellen Caluwé, Robert E Tainsh, Daniel I Nathan, Kaitlin Allen, Peter Brouckaert, Jozef Bartunek, Marielle Scherrer-Crosbie, Kenneth D Bloch, Donald B Bloch, Stefan P Janssens, Emmanuel S Buys
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 26 Issue 4 Pg. 153-164 (02 01 2017) ISSN: 1557-7716 [Electronic] United States
• PMID: 27505125 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Reactive Oxygen Species
• Doxorubicin
• Soluble Guanylyl Cyclase

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, adverse effects)
• Cardiotoxicity
• Disease Models, Animal
• Doxorubicin (administration & dosage, adverse effects)
• Enzyme Activation (drug effects)
• Gene Expression
• Heart Diseases (etiology, metabolism, physiopathology)
• Mice
• Mice, Knockout
• Mutation
• Myocytes, Cardiac (metabolism)
• Reactive Oxygen Species (metabolism)
• Soluble Guanylyl Cyclase (blood, deficiency)
• Ventricular Dysfunction