Project Grant R01HL174922

DUAL TARGETING CHEMOKINE RECEPTORS PREVENTS CHEMOTHERAPY-INDUCED CARDIOTOXICITY - DOXORUBICIN (DOX) IS AN EFFECTIVE CHEMOTHERAPEUTIC DRUG TO TREAT CANCER. HOWEVER, DOX-INDUCED CARDIOTOXICITY (DICT) HAS LIMITED ITS USE. DEXRAZOXANE IS THE ONLY CURRENT FDA-APPROVED AGENT FOR PREVENTING DICT, BUT ITS CARDIOPROTECTIVE EFFECT IS INCOMPLETE AND THE SIDE EFFECTS ALSO LIMIT ITS USE. THUS, THE SEARCH FOR NEW CARDIOPROTECTIVE AGENTS FOR DICT CONTINUES. SDF-1 AND ITS RECEPTOR CXCR4 PLAY ESSENTIAL ROLES IN CARDIOVASCULAR DEVELOPMENT AND DISEASES. CONSTITUTIVE LOSS EITHER ONE OF THEM RESULTS IN PERINATAL LETHALITY PARTIALLY DUE TO CARDIAC SEPTUM DEFECTS. MYOCARDIAL SUPPLEMENT OF SDF-1 ATTRACTS STEM CELLS THAT EXPRESS CXCR4 TO THE SITE OF INJURY TO PROMOTE CARDIAC REGENERATION AND ANGIOGENESIS. HOWEVER, THEIR ROLES IN CARDIOVASCULAR SYSTEM REMAIN CONTROVERSIAL. FOR INSTANCE, HETEROZYGOUS DELETION OF CXCR4 IN MICE REDUCED INFARCT SIZE AND CXCR4 OVEREXPRESSION INCREASED INFARCT SIZE AND REDUCED CARDIAC FUNCTION ALONG WITH EXCESSIVE CARDIAC INFLAMMATORY CELL INFILTRATION. CXCR7 IS A LATELY IDENTIFIED SECOND RECEPTOR FOR SDF-1. CXCR7 BINDS SDF-1 WITH AN AFFINITY ABOUT TEN TIMES HIGHER THAN CXCR4 AND IT CAN EITHER POSITIVELY OR NEGATIVELY AFFECT SDF-1/CXCR4 AXIS-MEDIATED FUNCTIONS. THIS RAISES A CONCERN AS TO HOW TO DISTINGUISH THE ROLES OF SDF-1/CXCR7 FROM SDF-1/CXCR4 IN CARDIAC PROTECTION. WE SHOWED THAT SDF-1 PREVENTS CARDIAC LIPOTOXICITY THROUGH CXCR7 BUT NOT CXCR4. A SINGLE- CELL RNA-SEQ ANALYSIS REVEALED THE MOST ABUNDANT EXPRESSION OF CXCR7 IN CARDIOMYOCYTES AND CARDIOMYOCYTE- SPECIFIC CXCR7 DELETION SHOWED MORE PROMINENT CARDIAC DYSFUNCTION AFTER MYOCARDIAL INFRACTION, SUGGESTING AN ESSENTIAL CARDIAC PROTECTION. GIVEN THE PROTECTIVE EFFECTS OF CXCR7 IN CARDIOMYOCYTES AND THE HARMFUL EFFECTS OF CXCR4-MEDIATED CARDIAC EXCESSIVE INFLAMMATION, WE TESTED THE PROTECTIVE EFFECTS OF A DUAL TARGETING COMPOUND WITH SPECIFIC ANTAGONISTIC ACTIVITY AGAINST CXCR4 AND POTENT AGONISTIC ACTIVITY ON CXCR7, AGAINST DICT. WE FOUND THIS COMPOUND TREATMENT SIGNIFICANTLY PREVENTED DOX-INDUCED CARDIAC DYSFUNCTION, CELL DEATH, INFLAMMATION AND FIBROSIS, ALONG WITH UPREGULATION OF SIGNALS INVOLVING IN CARDIAC ENERGY RESERVE METABOLIC PROCESS AND DOWNREGULATION OF SIGNALS INVOLVING IN MAST CELL INFILTRATION AND ACTIVATION, BUT WITHOUT AFFECTING THE SUPPRESSIVE EFFECTS OF DOX ON TUMOR GROWTH. WE THUS HYPOTHESIZE THAT DUAL TARGETING COMPOUND PREVENTS DICT BY ACTIVATING CARDIAC CXCR7 TO REPROGRAM CARDIOMYOCYTE METABOLISM AND PREVENT CARDIAC DYSFUNCTION AND BY ANTAGONIZING CXCR4 TO INHIBIT CARDIAC MAST CELL INFILTRATION AND ACTIVATION BUT WITHOUT AFFECTING THE SUPPRESSIVE EFFECTS OF DOX ON TUMOR GROWTH. THIS HYPOTHESIS WILL BE TESTED THROUGH SPECIFIC AIMS: 1) OPTIMIZING THE PROTECTIVE EFFECTS AGAINST DICT IN TUMOR-FREE AND TUMOR-BEARING MICE; 2) DETERMINING WHETHER IT PREVENTS DICT THROUGH ACTIVATING CXCR7/AMPK AND PREVENTS CARDIAC CELL DEATH AND DYSFUNCTION; 3) DETERMINING WHETHER IT PREVENTS DICT THROUGH INHIBITING CXCR4-MEDIATED CARDIAC MAST CELL INFILTRATION AND ACTIVATION. SUCCESSFUL COMPLETION OF THIS PROJECT WILL REVEAL NEW INSIGHT INTO THE UNDERLYING MECHANISMS BEHIND AND PROVIDE FUNDAMENTAL EVIDENCE FOR IT AS A NOVEL APPROACH FOR PREVENTING DICT IN FUTURE CLINICAL STUDIES.