Project Grant R01HL171366

FACTOR XIIA IS THE LONG-SOUGHT ACTIVATOR OF CIRCULATING RENIN IN HEART FAILURE. - HEART FAILURE (HF) IS A COMMON CAUSE OF PROGRESSIVE DISABILITY AND DEATH. INCREASED PLASMA RENIN ACTIVITY (PRA) LEVELS ARE AMONG THE EARLIEST BIOMARKERS AND MODULATORS OF HF WITH REDUCED EJECTION FRACTION (REF). RENIN IS A PROTEASE THAT ACTIVATES THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) TO REGULATE SALT-WATER HOMEOSTASIS, MYOCARDIAL CONTRACTILITY, BLOOD PRESSURE, AND VASCULAR WALL INTEGRITY. CHRONIC OVERACTIVATION OF THE RAAS HARMS THE HEART AND CIRCULATORY SYSTEM, PROMOTES SALT-WATER RETENTION (EDEMA) AND CARDIAC REMODELING, AND CONTRIBUTES TO EARLY MORTALITY IN HFREF. RENIN ITSELF IS ACTIVATED BY THE CLEAVAGE OF PRO-RENIN, BUT DESPITE ITS CRUCIAL ROLE AS A MASTER REGULATOR OF RAAS, THE MECHANISM(S) RESPONSIBLE FOR PRO-RENIN ACTIVATION IN THE CIRCULATION REMAIN UNKNOWN. INSIGHTS INTO THE MECHANISM OF SYSTEMIC RENIN ACTIVATION COULD LEAD TO NOVEL STRATEGIES TO PREVENT HFREF PROGRESSION AND DEATH. WE RECENTLY DISCOVERED A NOVEL HARMFUL ROLE OF PROTEINASE FACTOR XIIA (FXIIA) IN HFREF. WE HYPOTHESIZED THAT IN DILATED CARDIOMYOPATHY (DCM), FXIIA CONTRIBUTES TO THE DEVELOPMENT OF PROGRESSIVE HF IN VIVO AND THAT THE ADVERSE EFFECTS OF FXIIA MAY BE MEDIATED THROUGH ITS ENZYMATIC CLEAVAGE OF PRO-RENIN IN CIRCULATION. TO CONFIRM OR REFUTE OUR HYPOTHESES, WE WILL COMBINE ENZYMOLOGY, BIOMARKER ANALYSIS, AND HFREF MODELING IN VIVO WITH RELEVANCE TO HUMAN DISEASE. TO UNDERSTAND THE MECHANISM OF FXIIA IN DCM- HF, WE WILL IMPLY FXII-TARGETING MOLECULAR INTERVENTIONS AND PERFORM RANDOMIZED, BLINDED TRIALS TO LONGITUDINALLY EVALUATE CARDIAC DYSFUNCTION, EDEMA, CACHEXIA, AND OTHER DETRIMENTAL PHYSIOLOGICAL OUTCOMES AND CLINICALLY- RELATIVE BIOMARKERS OF HFREF. WE WILL EXPLORE OUR HYPOTHESES IN TWO SPECIFIC AIMS: 1) DEFINE THE NEWLY DISCOVERED ROLE OF FXIIA IN MODULATING THE PROGRESSION OF DCM AND HFREF; 2) TEST THE HYPOTHESIS THAT IN DCM, FXIIA ENHANCES THE PROGRESSION OF HFREF THROUGH INCREASED LEVELS OF PRA TO ACTIVATE RAAS. COMPLETING THE PROPOSED STUDY WILL DEFINE THE MECHANISMS OF FXIIA'S CONTRIBUTION TO HFREF AND DISCOVER NOVEL THERAPEUTIC STRATEGIES NEEDED TO BLOCK OR PREVENT THE PROGRESSION OF HFREF.