Abstract 18928: Cardiac Soluble Guanylate Cyclase Protects Against Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice

Abstract

Background - The chemotherapeutic use of doxorubicin (DOX) is limited by cardiotoxicity. Growing evidence suggests a protective role for cyclic guanosine monophosphate (cGMP) in pathological LV remodeling. We therefore tested the hypothesis that reduced cGMP bioavailability in cardiac myocytes worsens myocardial dysfunction in mice after chronic DOX treatment. Methods and Results - We generated mice with an inducible (Tet-Off) cardiac myocyte-specific expression of a dominant-negative soluble guanylate cyclase (dnsGC) mutant, which inhibits sGC signaling selectively in the heart. Cardiac cGMP levels, measured using an enzyme immunoassay, were lower in dnsGC mice (n=10) than in WT littermates (n=20) 5 minutes after administration of the NO-donor GSNO (1mg/kg) (0.99±0.34 vs 1.85±0.17 nmol/mg protein, respectively, P<0.05). At baseline, transthoracic echocardiography (TTE) demonstrated similar LV dimensions and function in dnsGC and WT (data not shown). Heart to body weight ratio was also comparable (HW/BW; 4.3±0.2 mg/g in dnsGC, n=13, vs 3.9±0.1 mg/g in WT, n=21). After 12 weeks DOX (2 mg/kg weekly), LV function was significantly reduced and LV diameters significantly enlarged as compared to saline-treated WT (Table). The impact of DOX on cardiac function and dimensions was more marked in dnsGC than in WT (P<0.05 for both, Table). Survival was similarly impaired in DOX-treated dnsGC (67%, n=30) and WT (59%, n=24) compared with saline-treated WT (100%, n=25). HW/BW was similar in DOX-treated dnsGC and WT (4.3±0.1 vs 4.2±0.1 mg/g), as was the % bromodeoxyuridine (BrdU)-positive cardiac myocytes or cardiac progenitor cells (0.8±0.4%, n=7 vs 1.6±0.7%, n=9, respectively, P=NS). Conclusions - Reduced myocardial cGMP results in increased LV dysfunction and dilatation in doxorubicin-treated mice. Stimulation of sGC activity in cardiac myocytes may represent a promising therapeutic approach for doxorubicin cardiotoxicity.