Targeted cardiac inactivation of Guanylate binding protein 5 (GBP5) protects from cardiotoxicity after doxorubicin treatment

Background The inflammasome pathway is known to play a crucial role in immune cell-driven cardiac stress response while the role in cardiomycoytes is not well investigated. In a cell culture model, using neonatal rat cardimoyocytes (NRVMS), we identified GBP5 (guanylate binding protein 5), a mediator of inflammasome activation, upregulated after doxorubicin treatment in a concentration-dependent manner. The NLRP3 inflammasome, a complex responsible for triggering the release of pro-inflammatory cytokines, including IL-1β and IL-18 is known to depend on GBP5. Methods To investigate GBP5 as a potential drug target, we generated an inducible, conditional, cardiomyocyte-specific knock-in mouse, expressing a dysfunctional GBP5 molecule (GBP5-cKI), lacking the c-terminus which is necessary for NLRP3 assembly. To explore its in vivo role, C57BL/6N were treated with 3 mg/kg of bodyweight doxorubicin i.p. every 2 days (8 injections). Mice were sacrificed 4 weeks after the last injection Results GBP5-cKI were protected from doxorubicin related mortality with a markedly prolonged survival compared to wild-type controls (p<0.001). Furthermore, cardiac function was largely preserved after doxorubicin treatment in GBP5-cKI. FS 26.07% ± 1.0 vs. 21.94% ± 1.3 GBP5-cKI vs. WT controls; p<0,01; EF 51.20% ± 1.7 vs. 44.45 ± 2.2 GBP5-cKI vs. WT controls; p<0.01). GBP5-cKI showed lower levels of Caspase-1 and IL1b activation. Interestingly the lung/body ratio was significantly elevated in wildtype animals only, indicating a phenotype of congestive heart failure. Implications: These results suggest that the C-terminal GBP5 is required for the doxorubicin-dependent activation of the inflammasome pathway, highlighting GBP5 as a new potential therapeutic target to reduce cardiac damage after doxorubicin therapy