Abstract
Background: Dose-dependent declines in left ventricular ejection fraction (LVEF) and increases in heart failure (HF) limit the administration of doxorubicin [DOX] in the treatment of breast cancer, lymphoma, and leukemia. Cancer patients with hypertension (HTN) experience higher rates of developing HF after DOX and perhaps share mechanistic contributors (e.g., oxidative stress and inflammation) to LVEF declines. Hydrogen sulfide (H 2 S) has been shown to stimulate mitochondrial stability and reduce the residual inflammatory risk in the setting of myocardial infarction. Hypothesis: The orally active, slow-releasing H 2 S donor SG1002 attenuates DOX-induced LVEF decline and cardiotoxicity in mice with HTN. Methods: Adult female C57BL mice were randomized to either control diet or SG1002-enriched chow to achieve a dosage of 40 mg/kg/day for the duration of the study. Mice underwent osmotic minipump implantation to deliver angiotensin II (ATII) (1500ng·kg -1 ·min -1 ; N=7/group) for 28 days to cause HTN. Seven days following ATII infusion initiation, DOX was delivered i.p., 4 doses of 5 mg/kg every 3 days (cumulative dose: 20mg/kg). Mice underwent tail-cuff blood pressure measurement and echocardiography at baseline, 12 days (post 2 nd DOX dose) and 28 days post initiation of ATII infusion (Fig A). Results: Twenty-eight-day measures in LVEF were lower in HTN animals receiving DOX relative to those without HTN. SG1002-fed mice demonstrated preserved LVEF following DOX (Fig B). Additionally, SG1002-fed mice exhibited an attenuated hypertensive phenotype following ATII infusion (Fig C). Conclusion: Our results in female mice indicate that HTN worsens DOX-induced cardiomyopathy, which is attenuated with SG1002 treatment. Interestingly, SG1002 also prevented HTN following ATII infusion in female mice. Further studies are warranted to determine the efficacy of the H 2 S donor, SG1002 to prevent DOX-associated LVEF declines in mice with and without HTN.
Published Version
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