Hydrogen Sulfide Donor Inhibits Cisplatin-induced Foam Cell Death In An In Vitro Model Of Atherosclerosis

Introduction: Cisplatin (CPDD) is used to treat various cancers, including testicular, lung, head and neck, and ovarian. CPDD use is associated with long-term cardiovascular morbidity and mortality risk, including acute coronary syndrome (ACS). Pro-inflammatory activation and death of macrophage foam cells (MFC) within the atheroma contribute to plaque destabilization and coronary artery thrombosis. The mechanisms underlying CPDD-induced ACS remain largely obscure. Hydrogen sulfide (H 2 S) has been shown to regulate cell survival and reduce the residual inflammatory risk in the setting of myocardial infarction. Hypothesis: We hypothesize that H 2 S protects MFC following CPDD administration. Methods: Human monocyte THP-1 cells were differentiated into MFC with 150 nM of phorbol 12-myristate 13 acetate (PMA) for 48 hours, followed by 100 μg/mL of OxLDL in serum-free media for 24 hours. Lipid content was assessed by Oil Red O staining (Fig A). A Methyl thiazolyl diphenyl-tetrazolium bromide (MTT) assay was used to assess the cytotoxic effects on MFC subjected to 24-hour treatment with 25 μM CPDD following 30-minute pre-treatment with 40 μM sodium sulfide (Na 2 S, a H 2 S donor) (Fig B). Results: Differentiated cells exposed to OxLDL showed a 25% increase in lipid accumulation compared to untreated cells (Fig A, **p<0.01 vs THP-1). Na 2 S alone showed no effect on cell death. Treatment with CPDD induced ~20% increase in cell death while pre-treatment with Na 2 S reduced MFC death by ~50% (Fig B, **p<0.01 vs OxLDL, *p<0.05 vs OxLDL+CPDD). Conclusion: Our results indicate that CPDD may contribute to plaque destabilization by inducing MFC death, which is attenuated with H 2 S treatment.