Project Grant R01HL172888

TARGETED APPROACH TO THE MITIGATION OF ABDOMINAL AORTIC ANEURYSM - PROJECT SUMMARY ABDOMINAL AORTIC ANEURYSM (AAA) IS CHARACTERIZED BY PROGRESSIVE AORTIC DILATION AND RUPTURE THAT LEADS TO SUDDEN DEATH. TO DATE, THERE ARE NO MEDICINAL THERAPIES TO STOP AAA FROM PROGRESSING TO RUPTURE, LARGELY DUE TO POOR UNDERSTANDING OF NOT ONLY EFFECTIVE MOLECULAR TARGETS BUT ALSO TARGETED DELIVERY APPROACHES. WHILE STUDIES HAVE TRADITIONALLY FOCUSED ON IMMUNE CELLS AND ENDOTHELIAL CELLS, SMOOTH MUSCLE CELLS (SMCS) CAN UNDERGO INFLAMMATION AND DEGENERATION, AND EXACERBATE AAA VIA SECRETION OF PROINFLAMMATORY CYTOKINES AND PROTEOLYTIC ENZYMES. THUS, CONTROLLING SMC INFLAMMATION AND DEGENERATION HAS THE POTENTIAL TO MITIGATE AAA. PREVIOUSLY OUR LAB IDENTIFIED BROMODOMAIN PROTEIN-4 (BRD4) AS A DRIVER OF SMC INFLAMMATION. BRD4 IS A TRANSCRIPTION CO- ACTIVATOR THAT RECOGNIZES HISTONE ACETYLATION SITES WHERE IT FACILITATES THE CLUSTERING OF TRANSCRIPTION ENHANCERS INTO SUPER-ENHANCERS, THEREBY MEDIATING GENE ACTIVATION. OUR TEAM HAS DEMONSTRATED THAT PAN-INHIBITION OF BRD FUNCTION AMELIORATES AAA IN MICE, HOWEVER THE MECHANISMS THAT UNDERLIE THE SPECIFIC ROLE OF BRD4 IN CONTROLLING AAA-ASSOCIATED SMC INFLAMMATION AND DEGENERATION REMAIN LARGELY UNKNOWN. HERE WE PRESENT PROMISING FINDINGS THAT REVEAL AN IMPORTANT PHYSIOLOGICAL FUNCTION OF BRD4 IN MODULATING AAA PROGRESSION. USING CULTURED SMCS, WE FIND THAT BRD4 PROTEIN IS INCREASED UPON EXPOSURE TO PRO-INFLAMMATION FACTORS; AND HUMAN LESIONS OF AAA ALSO SHOW ELEVATED BRD4 EXPRESSION. MICE WITH SMC-SPECIFIC KNOCKOUT OF BRD4 DEVELOP RESISTANCE TO ELASTASE-INDUCED AAA, SUGGESTING A POTENTIAL PRO-ANEURYSM ROLE OF BRD4. GENOME-WIDE ANALYSIS REVEAL BRD4 ENRICHMENT AT THE GENE OF CCAAT ENHANCER BINDING PROTEIN DELTA (CEBPD), A MASTER TRANSCRIPTION FACTOR THAT CONTROLS SMC INFLAMMATION AND DEGENERATION. IN ELASTASE-INDUCED AAA MODELS, KNOCKDOWN OF CEBPD REDUCES AAA SIZE; CONVERSELY, OVEREXPRESSION OF CEBPD IN THE SMC-SPECIFIC BRD4 KNOCKOUT AORTA EXACERBATES AAA IN MICE. OVERALL, THESE FINDINGS SUPPORT THE PREMISE THAT BRD4/CEBPD MAY PARTICIPATE IN THE EPIGENETIC CONTROL OF GENES INVOLVED IN SMC DEGENERATION AND INFLAMMATION ASSOCIATED WITH AAA. BY RESOLVING THE PHYSIOLOGIC ROLE, AND THE CELLULAR AND MOLECULAR UNDERPINNINGS OF BRD4-CEBPD-AAA, WE CAN ADVANCE THE PATHOPHYSIOLOGY OF AAA, AND POTENTIALLY GAIN NOVEL THERAPEUTIC APPROACHES TO TREAT AAA. OUR TEAM HAS DEVELOPED A NOVEL BIOMIMETIC AAA-HOMING NANOPLATFORM. WE ENVISION THAT TARGETED DELIVERY OF BRD4-INACTIVATING AGENTS CAN PROVIDE A POTENTIAL EFFECTIVE MEANS TO MITIGATE AAA.