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The Potential Rationale for BET Inhibition in Management of CVD

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The Potential Rationale for BET Inhibition in Management of CVD Understanding epigenetics: The potential rationale for BET inhibition in management of CVD August 25, 2018 Munich, Germany Jorge Plutzky, MD Director, Preventive Cardiology Cardiovascular Division Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Coordinated Programs In Cardiometabolic States? Physiology Pathology • Fit • Central obesity • Normotensive • Diabetes • Insulin sensitivity • Hypertension • Less inflammation • Inflammation • Longevity • Alzheimer’s Disease • Cancer + - - + Gene A Gene C Gene J Gene X Gene Z Coordinated Programs In Cardiometabolic States? Physiology CV Disease • Fit • Central obesity • Normotensive • Diabetes • Lower Triglycerides • Hypertension • Higher HDL • Hypertriglyceridemia • Insulin sensitivity • Low HDL • Less inflammation • Insulin resistance • Endothelial function • Inflammation • Longevity • Endothelial dysfunction Modulating key proximal transcription factors • Coagulation • Myocardial injury + - - + Gene A Gene C Gene J Gene X Gene Z Energy Balance PPAR RXR Energy Balance Lipids: Glucose Triglycerides (Fatty Acids) Obesity PPAR RXR Dyslipidemia Diabetes Inflammation Atherosclerosis PPARs in Transcriptional Regulation PPARs and Gene Regulation LPS Cytokines Matrix Lipids AngII AGEs Hemodynamics A key integrator of inflammation NF-kB and atherosclerosis Inflammatory targets Collins, Cybulsky JCI 2001 ChallengesPPARs inin Transcriptional Regulation - Store PPARsvast genetic and material Gene in nucleus Regulation - Access specific genetic stretches to enable transcription 10,000 fold 2 nm decrease in size 30 nm 300 nm 700 nm 1400 nm Transcription Factors Heterochromatin Transcription impeded Euchromatin Transcription Factor Access Transcription Possible CHROMOSOME FIBRE NUCLEOSOME EPIGENETIC CODE DNA histone mark chromatin fibre Plutzky, El Assam, Circ Res, 2016 CHROMOSOME FIBRE NUCLEOSOME EPIGENETIC CODE DNA acetylases, methylases phosphylases… histone mark deacetylases, demethylases dephosphylases… chromatin fibre Plutzky, El Assam, Circ Res, 2016 CHROMOSOME FIBRE NUCLEOSOME EPIGENETIC CODE DNA histone mark Acetylated lysines: BETs chromatin fibre Plutzky, El Assam, Circ Res, 2016 Coordinated Programs In Cardiometabolic States? Physiology CV Disease • Fit • Central obesity • Normotensive • Diabetes • Low TG/High HDL • Hypertension • Insulin sensitivity • High TG/ Low HDL • Less inflammation • Inflammation • Endothelial function • Endothelial dysfunction • Longevity • Coagulation • Myocardial injury Epigenetics: BETs Master Protein Transcription Factors mRNA Enhancers Promoters Gene J Gene X Gene Z Response elements Bromodomains • Structural motif (110 aa) • Interacts with acetylated lysines on histones • ~50 bromodomain-containing protein family Bromodomain and Extra-Terminal Domain (BETs): Sub-family of proteins containing tandem bromodomains 1 74-185 345-457 632-710 801 BRD2 BD BD E 1 2 T 1 34-145 307-419 562-640 726 BRD3 BD BD E 1 2 T 1 58-159 349-461 600-678 1362 BRD4 BD BD E 1 2 T 1 27-138 268-380 500-578 947 BRDT* BD BD E 1 2 T BET Proteins: Integral to Transcription Complex Assembly Along Gene Body BET BET Protein Inhibitor Selectivity BET Protein 4 (BRD4) BET Inhibitor Nature Reviews Mol Cell Biology 13, 543-547 16 Bradner, Nature 2010 Current Issues in Epigenetics/BETs: Super Enhancers Cell States: Transformation Health Disease Differentiation Activation Adaptation Maladaptive Epigenetics Pathologic BETs Therapeutic? Programs that define cell state Organ: functional, dynamic Cell States Interface: Circulation + Organs Transducer Endothelium Rest Cell State Transitions Inflammation Multiple stimuli: Physical, chemical Cell States Rapid Reset Pathologic Essential: Host defenses Endothelium Rest Inflammation Cell State Transitions Transcriptional Programs Super-Enhancers BET Epigenetic Readers Chromatin Remodeling DIABETES Genetics Cell States Exposures Hyperglycemia : Cig AGEs HTN Dyslipidemia Maternal- Fetal Inflammation Diet NFkB Epigenetic Readers: BETs Modified, Reddy, Natarajan, Epigenetics: Development & Disease, Subcellular Biochemistry 61, p435, 2013 Pressure Overload: BET Bromodomains Mediate Cell States Transcriptional Pause Release In Heart Failure Transverse Aortic Constriction Anand, Brown, Plutzky, Bradner, Haldar et al Cell 154: 569-582, 2013 BET bromodomain inhibition significantly decreases LDLr -/- atherosclerosis VEH JQ1 VEH JQ1 6 6 a 4 * e a 4 r * e A - 12 Weeks of HC/HF Diet r A n o n i - JQ1 50mg/kg, IP daily o s i 2 e s 2 L e L % % 0 0 VEH JQ1VEH JQ1 Oil Red O Mac3 CD4 VCAM1 H E V Brown, Plutzky et al 1 Q J Mol Cell, 2013 Chromatin Immunoprecipitation coupled with deep sequencing: ChIP-Seq Crosslink Enrich for protein to Massively Harvest cells protein-bound DNA binding parallel DNA and fragment DNA fragments sites in living sequencing DNA with antibodies cells or tissue: Myocardium Endothelium TNF-a induces BRD4 recruitment to specific EC enhancers, enabling execution of the inflammatory NFkB transcriptional program - TNFa p65 + TNFa Start site - TNFa BRD4 + TNFa VCAM1 TNF-a induces BRD4 recruitment to specific EC enhancers, enabling execution of the inflammatory NFkB transcriptional program TNFa gained SE 10.0 p65 ChIP-Seq 10kb p b / TNFa (-) m p r 10.0 TNFa (+) 10.0 BRD4 ChIP-Seq p b / TNFa (-) m p r 10.0 TNFa (+) 3.0 H3K27ac ChIP-Seq p b / TNFa (-) m p r 3.0 TNFa (+) 3.5 H3K4me3 ChIP-Seq p b / TNFa (-) m p r Chemokine 3.5 TNFa (+) 15.0 RNA Pol II ChIP-Seq CCL2 p b / TNFa (-) m p r 15.0 TNFa (+) chr17:29,571,987 chr17:29,622,217 CCL2 directs directs of super remodeling rapid Dynamic, a broad, canonical canonical a broad, pro - atherosclerotic atherosclerotic - enhancers in enhancers Change in BRD4 Log TNFa (+) vs. TNFa (-) program l 2 a −5 0 5 n g i 0 s s Ecs E 4 S D d R SELE e B n i VCAM1 n a i g e 100 CCL2 a g F n a N h T c y n=152 b d e 200 k n a r s C E n i 300 s n o i g e n=124 r r s e E c 400 S n t a s h o n l SOX18 e a − F r e N p T u 500 S Apabetalone Reduces Atheroma in Aorta of ApoE-/- Mice Chow High Fat (42% kcal) Diet Chow: TD 2016 +/- WK WK WK apabetalone WK 33 8 9 19 Animal HF Diet Chow Diet Necropsy Arrival Whole aorta Aortic sinus Placebo Apabetalone 20 of -31% of -40% (p<0.016) 11.081-607-040 15 (p<0.045) Whole aorta 15.081-608-519 SE 10 - (%) +/ (%) 5 Plaque/whole area area Plaque/whole 8.092-895-111 16.040-776-379 Aortic Aortic sinus 0 Placebo PlaceboApabetalone Apabetalone (150 mg/kg) (150 mg/kg) Jahagirdar Atherosclerosis 2015 28 Tandem BET bromodomains allows for inhibitor selectivity: Distinct expression effects: Apabetalone (selective) vs. JQ-1 (pan) BET inhibition (+)- JQ1 (+)- JQ1 (+)- JQ1 PNAS, 2013 110 (49):19754-9. 29 BRD4 Regulates the Adipogenic Program BRD4: Log D2 vs D0 Pre-Adipo DAY 0 PPARg CEBPa PTN PPARg Adipo DAY 2 PPARg PTN PTN PNAS, 2018 Enhancers Ranked By BRD4 Signal BETBET Inhibition Action Pathologic Transcriptional Programs Cardiovascular: Inflammation: Metabolism: MF T cells Cardiomyocytes ECs VSMCs Pltlets Adipocytes b Cells Renal: Hepatocytes Tubular BETBET Inhibition Action cells Apabetalone Inflammation Injury Indirect Direct Indirect Atherosclerosis Pathologic Transcriptional Programs .
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