Therapeutic RNA regulation during cardiac remodeling and disease

Abstract

Cardiovascular diseases (CVDs) are diseases that affect the heart and blood vessels and to date, there is no cure. The only available clinical practices to manage CVDs are suggesting lifestyle changes, exercise-based cardiac rehabilitation, symptom management with medication, surgical intervention to prevent sudden cardiac arrest, or heart transplantation in case of end-stage heart failure. In this thesis we performed studies to extend our knowledge on 1) cardiac-specific gene regulation pathways relevant during CVDs and 2) new therapeutic approach to deliver pharmacological agents in the heart cells to treat ischemic heart disease. To do so, we sequenced the RNA of cardiomyocytes isolated from mouse models of cardiac pathological and physiological hypertrophy, we used in vitro cardiac models to identify and investigate the role of novel gene targets. Additionally, we studied the safety and efficacy of a hydrogel-based delivery method to increase local delivery of miRNA therapeutics to cardiomyocytes in a mouse model of ischemic heart disease. Our results showed that cardiomyocytes at various stages of cardiac remodeling present remarkably diverse genetic profiles and that these genetic profiles have a potentially relevant role in regulating heart remodeling, from metabolic switch to transcription factors to miRNAs. At therapeutic level, we show that we can intervene using RNA therapeutics and hydrogel-based delivery. Thesis outline The studies described in this thesis were aimed to extend our insights on CM-specific gene regulation relevant for cardiac remodeling and to study a novel therapeutic approach for CM-specific delivery. In chapter 2 we investigate CM-specific gene programs in pathological remodeling. Using a model of pressure overload, we identified a failure-induced gene program, which is conserved between mouse and human. Here, we identified phosphofructokinase-platelet isoform (PFKP) to play a role in CM remodeling during HF. In chapter 3 we investigate CM-specific gene programs driving physiological hypertrophy. Using a model of swimming, we identified the exercise-induced gene program in CMs. By focusing on transcription factors, we identified high expression of Sox17 in hypertrophic CMs. We investigated the potential cardioprotective role of Sox17 in a model of pressure overload by using adenoviral delivery which failed to preserve cardiac function during pathology. In chapter 4 we investigate the efficacy and safety of a new hydrogel-based delivery system in a model of ischemic injury. Hydrogel-based delivery of antimir-195 improved CM local delivery and enhanced target de-repression and CM proliferation. Finally, in chapter 5 we discuss all findings in a broader context together with future perspectives.