Cardiotoxicity remains a major limitation in the clinical utility of anthracycline chemotherapeutics. Regulator of G-protein Signaling 7 (RGS7) and inflammatory markers are up-regulated in the hearts of patients with a history of chemotherapy particularly those with reduced left-ventricular function. RGS7 knockdown in either the murine myocardium or isolated murine ventricular cardiac myocytes (VCM) or cultured human VCM provided marked protection against doxorubicin-dependent oxidative stress, NF-κB activation, inflammatory cytokine production, and cell death. In exploring possible mechanisms causally linking RGS7 to pro-inflammatory signaling cascades, we found that RGS7 forms a complex with acetylase Tip60 and deacetylase sirtuin 1 (SIRT1) and controls the acetylation status of the p65 subunit of NF-κB. In VCM, the detrimental impact of RGS7 could be mitigated by inhibiting Tip60 or activating SIRT1, indicating that the ability of RGS7 to modulate cellular acetylation capacity is critical for its pro-inflammatory actions. Further, RGS7-driven, Tip60/SIRT1-dependent cytokines released from ventricular cardiac myocytes and transplanted onto cardiac fibroblasts increased oxidative stress, markers of transdifferentiation, and activity of extracellular matrix remodelers emphasizing the importance of the RGS7-Tip60-SIRT1 complex in paracrine signaling in the myocardium. Importantly, while RGS7 overexpression in heart resulted in sterile inflammation, fibrotic remodeling, and compromised left-ventricular function, activation of SIRT1 counteracted the detrimental impact of RGS7 in heart confirming that RGS7 increases acetylation of SIRT1 substrates and thereby drives cardiac dysfunction. Together, our data identify RGS7 as an amplifier of inflammatory signaling in heart and possible therapeutic target in chemotherapeutic drug-induced cardiotoxicity.
Keywords: Acetylation; Cardiotoxicity; Chemotherapy; Fibrosis; Inflammation; RGS proteins.
© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.