Project Grant F31HL189138

THE ROLE OF THE ENDOTHELIAL CIRCADIAN CLOCK IN DOXORUBICIN-INDUCED CARDIOTOXICITY - ABSTRACT CARDIOVASCULAR DISEASE (CVD) IS A LEADING CAUSE OF MORBIDITY AND MORTALITY AMONG CANCER SURVIVORS, PARTICULARLY THOSE TREATED WITH ANTHRACYCLINES SUCH AS DOXORUBICIN (DOXO), WHICH ARE KNOWN TO INDUCE LONG-TERM CARDIOTOXIC EFFECTS INCLUDING ENDOTHELIAL DYSFUNCTION, CARDIOMYOPATHY, AND HEART FAILURE. DESPITE THE WIDESPREAD USE OF ANTHRACYCLINES IN PEDIATRIC AND ADULT ONCOLOGY, CURRENT STRATEGIES TO PREVENT CHEMOTHERAPY-INDUCED CARDIOVASCULAR TOXICITY REMAIN LIMITED, AND THE UNDERLYING MECHANISMS ARE POORLY UNDERSTOOD. EVIDENCE IMPLICATES THE CIRCADIAN CLOCK-A CRITICAL REGULATOR OF PHYSIOLOGICAL RHYTHMS-IN CARDIOVASCULAR HEALTH, WITH DEREGULATION LINKED TO ENDOTHELIAL DYSFUNCTION AND CVD. HOWEVER, ITS ROLE IN CHEMOTHERAPY-INDUCED CARDIAC INJURY, PARTICULARLY THROUGH EFFECTS ON ENDOTHELIAL CELLS-WHICH ARE ESSENTIAL FOR MAINTAINING VASCULAR HEALTH-HAS NOT BEEN FULLY ELUCIDATED. PRELIMINARY DATA FROM OUR LABORATORY DEMONSTRATE THAT DOXO EXPOSURE DISRUPTS CIRCADIAN CLOCK EXPRESSION IN HUMAN CORONARY ARTERY ENDOTHELIAL CELLS, WITH DOSE-DEPENDENT ALTERATIONS IN CORE CLOCK COMPONENTS SUCH AS BMAL1, CLOCK, PER1/2, AND CRY2, CORRELATING WITH MARKERS OF ENDOTHELIAL ACTIVATION, CELL CYCLE ARREST, AND APOPTOSIS. THESE FINDINGS SUGGEST THAT CIRCADIAN CLOCK DISRUPTION MAY BE A KEY CONTRIBUTOR TO DOXO-INDUCED ENDOTHELIAL TOXICITY. THE PROPOSED RESEARCH WILL INVESTIGATE THE CENTRAL HYPOTHESIS THAT ENDOTHELIAL CIRCADIAN CLOCK COMPONENTS ARE ESSENTIAL FOR MAINTAINING CARDIOVASCULAR HOMEOSTASIS UNDER CHEMOTHERAPEUTIC STRESS. AIM 1 WILL DETERMINE THE RELEVANCE OF THE CIRCADIAN CLOCK IN ENDOTHELIAL INJURY RESPONSE TO DOXORUBICIN EXPOSURE. AIM 2 WILL DEFINE THE IMPACT OF ENDOTHELIAL BMAL1 DEFICIENCY ON CARDIOVASCULAR HOMEOSTASIS IN RESPONSE TO DOXORUBICIN INDUCED CARDIOTOXICITY. COMPLETION OF THESE STUDIES WILL PROVIDE FOUNDATIONAL INSIGHTS INTO THE MOLECULAR MECHANISMS OF CHEMOTHERAPY-INDUCED CARDIOVASCULAR TOXICITY AND IDENTIFY NOVEL TARGETS FOR CARDIOPROTECTION ULTIMATELY ADVANCING STRATEGIES FOR PROMOTING CARDIOVASCULAR HEALTH IN CANCER SURVIVORS.