Hydrogen Sulfide for the Prevention of Cisplatin-Induced Atherosclerosis

About This Grant

Project Summary Cisplatin (CDDP) is a widely used chemotherapeutic used to treat various cancers, including testicular, lung, head and neck, and ovarian. CDDP use is associated with long-term cardiovascular morbidity and mortality risk, including acute coronary syndrome (ACS). Patients treated with CDDP-based therapies have demonstrated a higher prevalence of cardiovascular risk factors that contribute to the development of ACS. The induction of oxidative stress and pro-inflammatory signaling are known contributing factors in other pathologies of CDDP- induced toxicity. During atherosclerosis progression, pro-inflammatory activation promotes macrophage foam cell death; expansion of the necrotic core, and deterioration of the fibrous cap, resulting in plaque destabilization and coronary artery thrombosis. Hydrogen sulfide (H2S), a gasotransmitter, has gained therapeutic interest due to its known ability to reduce oxidative stress and inflammation. However, H2S has not been studied for its potential to treat CDDP-induced ACS, thus we will assess its protective effects against CDDP-induced plaque instability in a model of atherosclerosis. Based on my preliminary results, I hypothesize that CDDP-induced ROS and inflammation promote macrophage foam cell necroptosis, which may be attenuated by H2S. Our preliminary data support that CDDP induces macrophage foam cell death, which is attenuated by Nec-1, a necroptosis inhibitor, and GYY4137, an H2S donor. We will first assess the activation of necroptosis in CDDP-treated macrophage foam cells by western blot, ELISA, and siRNA knockdown of necroptotic mediators. Furthermore, we will evaluate the ability of H2S to attenuate CDDP-induced cell death. Second, we hypothesize that CDDP administration increases plaque vulnerability in vivo, which may be attenuated with an orally administered H2S donor, SG1002. To test our hypothesis, we will use Ldlr knockout mice placed on a high-fat diet as a model of atherosclerosis. A repeated low-dose model of CDDP toxicity will be used (weekly i.p. injections, for 4 weeks). We will perform aortic dissections to conduct histological and immunocytochemical analysis to assess plaque burden, necrotic core area, fibrous cap thickness, and macrophage-to-smooth muscle ratio. We will then determine the impact of SG1002 administration on the effects of CDDP on plaque vulnerability using the parameters mentioned previously. Identifying the molecular mechanisms contributing to CDDP-induced foam cell death and plaque instability will provide crucial insights into the link between CDDP-based regimens and ACS in cancer survivors. Furthermore, this proposal will present a novel therapeutic approach to circumvent CDDP-induced ACS, which can result in the clinical presentations of myocardial infarction in cancer survivors.