This R35 application proposes to capitalize on previous work produced by the PI over the past 11 years and to further serve as a strong foundation for interrogating the role of sterile cardiac inflammation (inflammasomes) in promoting the progression of heart failure caused by chemotherapy-induced cardiotoxicity and complicated with myocardial ischemia. The overarching goal of this program is to better understand how inflammasome formation/activation in the heart secondary to different stress signals perpetuates myocardial injury and also dissect the contributions of different cardiac cell types during this pathophysiologic process. 1) Previous studies from the PI?s lab have characterized the role of the inflammasome in mediating adverse cardiac remodeling following acute myocardial infarction in preclinical models. 2) Other studies from the PI?s lab also demonstrated that NLRP3 inflammasome inhibition reduced interstitial fibrosis and preserved systolic cardiac function in mice exposed to doxorubicin. Evidence from the literature also supports a pathophysiologic role of NLRP3 in mediating doxorubicin-induced cardiotoxicity. Moreover, studies from the PI?s lab and others have shown that endogenous production of hydrogen sulfide (H2S) is essential for survival during cellular stresses, including ischemia, and that administration of H2S donors further promotes survival. The orally-active H2S- donor SG1002 was shown in a recent Phase I clinical trial to be safe and tolerable in heart failure patients and also to increase blood H2S levels as well as circulating nitric oxide while attenuating BNP. We recently demonstrated that H2S treatment attenuates ischemic and inflammatory (NLRP3 inflammasome) injury following myocardial infarction. Accordingly, modulation of the inflammasome with H2S may represent an important mechanism to limit inflammatory cell death and mitigate cardiomyopathy. Preliminary data demonstrate that increases in cofilin-2 expression and its potential for phospohorylation and oxidation under oxidative stress rises during ischemic injury, which is attenuated with H2S donors. Thus, this proposal provides the opportunity to perform in-depth investigations on role of the cardiac inflammasome and structural proteins, such as cofilin2, in heart failure due to chemotoxicity and also when complicated with myocardial infarction, therefore extending our knowledge on the potential mechanism of cardiotoxicity and facilitating the design and development of novel preventive/therapeutic modalities in the emerging field of cardio-oncology.
The occurrence of heart failure in cancer survivors is devastating and continues to rise and is mostly due to the very therapies that were utilized to cure/mitigate cancer. The involvement of sterile inflammation (cardiac inflammasome) and post-translational modifications of some structural cardiac proteins in the development and progression of chemotherapy-induced cardiomyopathy in relation to mitochondrial dysfunction/oxidative stress or other signaling pathways remain rather understudied. In this proposed program, we seek to further explore the role of the cardiac inflammasome as it relates stress signals and potential maladaptive post-translational protein modifications in chemotherapy-induced cardiomyopathy by focusing on the cardiac cell-type involvement as well as novel potential therapeutic strategies to prevent and/or mitigate adverse cardiac remodeling and failure.
