Vandenwijngaert, SaraSwinnen, MelissaWalravens, Ann-SophieBeerens, ManuGillijns, HildeCaluwé, EllenTainsh, RobertNathan, Daniel I.Allen, KaitlinBrouckaert, PeterBartunek, JozefScherrer-Crosbie, MarielleBloch, KennethBloch, DonaldJanssens, Stefan P.Buys, Emmanuel2017-10-052017Vandenwijngaert, Sara, Melissa Swinnen, Ann-Sophie Walravens, Manu Beerens, Hilde Gillijns, Ellen Caluwé, 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) (February): 153–164. doi:10.1089/ars.2015.6542.1523-0864http://nrs.harvard.edu/urn-3:HUL.InstRepos:34060860Aims: 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 a1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGCa1 allele [sGCa1-/-CM]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGCa1-/-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 sGCa1 mutant (DNsGCa1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGCa1tg/+, but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGCa1tg/+ and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGCa1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGCa1-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.en-UScardiovascularcariomyopathychemotherapydoxorubicincyclic nucleotidessoluble guanylate cyclaseJournal Article2017-06-0120172017-10-0510.1089/ars.2015.6542