1  5891 123 SYSTEMS BIOLOGY IN CHRONIC HEART FAILURE-IDENTIFICATION OF POTENTIAL MIRNA REGULATORS. HEART FAILURE (HF) IS A COMPLEX DISEASE ENTITY WITH HIGH CLINICAL IMPACT, POORLY UNDERSTOOD PATHOPHYSIOLOGY AND SCANTLY KNOWN MIRNA-MEDIATED EPIGENETIC REGULATION. WE HAVE ANALYSED MIRNA PATTERNS IN PATIENTS WITH CHRONIC HF (CHF) AND A SEX- AND AGE-MATCHED REFERENCE GROUP AND PURSUED AN IN SILICO SYSTEM BIOLOGY ANALYSIS TO DISCERN PATHWAYS INVOLVED IN CHF PATHOPHYSIOLOGY. TWENTY-EIGHT MIRNAS WERE IDENTIFIED IN CHF THAT WERE UP-REGULATED IN THE REFERENCE GROUP, AND EIGHT OF THEM WERE VALIDATED BY RT-QPCR. IN SILICO ANALYSIS OF PREDICTED TARGETS BY STRING PROTEIN-PROTEIN INTERACTION NETWORKS REVEALED EIGHT CLUSTER NETWORKS (INVOLVING SEVEN OF THE IDENTIFIED MIRNAS) ENRICHED IN PATHWAYS RELATED TO CELL CYCLE, RAS, CHEMOKINE, PI3K-AKT AND TGF-BETA SIGNALING. BY ROC CURVE ANALYSIS, COMBINED PROBABILITIES OF THESE SEVEN MIRNAS (LET-7A-5P, MIR-107, MIR-125A-5P, MIR-139-5P, MIR-150-5P, MIR-30B-5P AND MIR-342-3P; CLUSTERS 1-4 [C:1-4]), DISCRIMINATED BETWEEN HF WITH PRESERVED EJECTION FRACTION (HFPEF) AND HF WITH REDUCED EJECTION FRACTION (HFREF), AND ISCHAEMIC AND NON-ISCHAEMIC AETIOLOGY. A COMBINATION OF MIR-107, MIR-139-5P AND MIR-150-5P, INVOLVED IN CLUSTERS 5 AND 7 (C:5+7), DISCRIMINATED HFPEF FROM HFREF. PATHWAY ENRICHMENT ANALYSIS OF MIRNAS PRESENT IN C:1-4 (LET-7A-5P, MIR-125A-5P, MIR-30B-5P AND MIR-342-3P) REVEALED PATHWAYS RELATED TO HF PATHOGENESIS. IN CONCLUSION, WE HAVE IDENTIFIED A DIFFERENTIAL SIGNATURE OF DOWN-REGULATED MIRNAS IN THE PLASMA OF HF PATIENTS AND PROPOSE NOVEL CELLULAR MECHANISMS INVOLVED IN CHF PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2  5437  38 REMOTE HIND-LIMB ISCHEMIA MECHANISM OF PRESERVED EJECTION FRACTION DURING HEART FAILURE. DURING ACUTE HEART FAILURE (HF), REMOTE ISCHEMIC CONDITIONING (RIC) HAS PROVEN TO BE BENEFICIAL; HOWEVER, IT IS CURRENTLY UNCLEAR WHETHER IT ALSO EXTENDS BENEFITS FROM CHRONIC CONGESTIVE, CARDIOPULMONARY HEART FAILURE (CHF). PREVIOUS STUDIES FROM OUR LABORATORY HAVE SHOWN THREE PHASES DESCRIBING CHF VIZ. (1) HF WITH PRESERVED EJECTION FRACTION (HFPEF), (2) HF WITH REDUCED EF (HFREF), AND (3) HF WITH REVERSED EF. ALTHOUGH RECIPROCAL ORGAN INTERACTION, ABLATION OF SYMPATHETIC, AND CALCIUM SIGNALING GENES ARE ASSOCIATED WITH HFPEF TO HFREF, THE MECHANISM IS UNCLEAR. THE HFREF ENSUES, IN PART, DUE TO REDUCED ANGIOGENESIS, CORONARY RESERVE, AND LEAKAGE OF ENDOCARDIAL ENDOTHELIAL (EE) AND FINALLY BREAKDOWN OF THE BLOOD-HEART BARRIER (BHB) INTEGRITY. IN FACT, OUR HYPOTHESIS STATES THAT A CHANGE IN PHENOTYPE FROM COMPENSATORY HFPEF TO DECOMPENSATORY HFREF IS DETERMINED BY A POTENTIAL DECREASE IN REGENERATIVE, PROANGIOGENIC FACTORS ALONG WITH A CONCOMITANT INCREASE IN EPIGENETIC MEMORY, INFLAMMATION THAT COMBINEDLY CAUSES OXIDATIVE, AND PROTEOLYTIC STRESS RESPONSE. TO TEST THIS HYPOTHESIS, WE CREATED CHF BY AORTA-VENA-CAVA (AV) FISTULA IN A GROUP OF MICE THAT WERE SUBSEQUENTLY TREATED WITH THAT OF HIND-LIMB RIC. HFPEF VS. HFREF TRANSITION WAS DETERMINED BY SERIAL/LONGITUDINAL ECHO MEASUREMENTS. RESULTS REVEALED AN INCREASE IN SKELETAL MUSCLE MUSCLIN CONTENTS, BONE-MARROW (CD71), AND SYMPATHETIC ACTIVATION (BETA2-AR) BY RIC. WE ALSO OBSERVED A DECREASE IN VASCULAR DENSITY AND ATTENUATION OF EE-BHB FUNCTION DUE TO A CORRESPONDING INCREASE IN THE ACTIVITY OF MMP-2, VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), CASPASE, AND CALPAIN. THIS DECREASE WAS SUCCESSFULLY MITIGATED BY RIC-RELEASED SKELETAL MUSCLE EXOSOMES THAT CONTAIN MUSCLIN, THE MYOKINE ALONG WITH BONE MARROW, AND SYMPATHETIC ACTIVATION. IN SHORT, BASED ON PROTEOME (OMICS) ANALYSIS, APPROXIMATELY 20 PROTEINS THAT APPEAR TO BE INVOLVED IN SIGNALING PATHWAYS RESPONSIBLE FOR THE SYNTHESIS, CONTRACTION, AND RELAXATION OF CARDIAC MUSCLE WERE FOUND TO BE THE DOMINANT FEATURES. THUS, OUR RESULTS SUPPORT THAT THE CHF PHENOTYPE CAUSES DYSFUNCTION OF CARDIAC METABOLISM, ITS CONTRACTION, AND RELAXATION. INTERESTINGLY, RIC WAS ABLE TO MITIGATE MANY OF THE DELETERIOUS CHANGES, AS REVEALED BY OUR MULTI-OMICS FINDINGS.	2021	
                                                                                                                                                                                                                                              
3  6569  26 TRANSPLANTATION OF EPIGENETICALLY MODIFIED ADULT CARDIAC C-KIT+ CELLS RETARDS REMODELING AND IMPROVES CARDIAC FUNCTION IN ISCHEMIC HEART FAILURE MODEL. CARDIAC C-KIT+ CELLS HAVE A MODEST CARDIOGENIC POTENTIAL THAT COULD LIMIT THEIR EFFICACY IN HEART DISEASE TREATMENT. THE PRESENT STUDY WAS DESIGNED TO AUGMENT THE CARDIOGENIC POTENTIAL OF CARDIAC C-KIT+ CELLS THROUGH CLASS I HISTONE DEACETYLASE (HDAC) INHIBITION AND EVALUATE THEIR THERAPEUTIC POTENCY IN THE CHRONIC HEART FAILURE (CHF) ANIMAL MODEL. MYOCARDIAL INFARCTION (MI) WAS CREATED BY CORONARY ARTERY OCCLUSION IN RATS. C-KIT+ CELLS WERE TREATED WITH MOCETINOSTAT (MOCE), A SPECIFIC CLASS I HDAC INHIBITOR. AT 3 WEEKS AFTER MI, CHF ANIMALS WERE RETROGRADELY INFUSED WITH UNTREATED (CONTROL) OR MOCE-TREATED C-KIT+ CELLS (MOCE/C-KIT+ CELLS) AND EVALUATED AT 3 WEEKS AFTER CELL INFUSION. WE FOUND THAT CLASS I HDAC INHIBITION IN C-KIT+ CELLS ELEVATED THE LEVEL OF ACETYLATED HISTONE H3 (ACH3) AND INCREASED ACH3 LEVELS IN THE PROMOTER REGIONS OF PLURIPOTENT AND CARDIAC-SPECIFIC GENES. EPIGENETIC CHANGES WERE ACCOMPANIED BY INCREASED EXPRESSION OF CARDIAC-SPECIFIC MARKERS. TRANSPLANTATION OF CHF RATS WITH EITHER CONTROL OR MOCE/C-KIT+ CELLS RESULTED IN AN IMPROVEMENT IN CARDIAC FUNCTION, RETARDATION OF CHF REMODELING MADE EVIDENT BY INCREASED VASCULARIZATION AND SCAR SIZE, AND CARDIOMYOCYTE HYPERTROPHY REDUCTION. COMPARED WITH CHF INFUSED WITH CONTROL CELLS, INFUSION OF MOCE/C-KIT+ CELLS RESULTED IN A FURTHER REDUCTION IN LEFT VENTRICLE END-DIASTOLIC PRESSURE AND TOTAL COLLAGEN AND AN INCREASE IN INTERLEUKIN-6 EXPRESSION. THE LOW ENGRAFTMENT OF INFUSED CELLS SUGGESTS THAT PARACRINE EFFECTS MIGHT ACCOUNT FOR THE BENEFICIAL EFFECTS OF C-KIT+ CELLS IN CHF. IN CONCLUSION, SELECTIVE INHIBITION OF CLASS I HDACS INDUCED EXPRESSION OF CARDIAC MARKERS IN C-KIT+ CELLS AND PARTIALLY AUGMENTED THE EFFICACY OF THESE CELLS FOR CHF REPAIR. SIGNIFICANCE: THE STUDY HAS SHOWN THAT SELECTIVE CLASS 1 HISTONE DEACETYLASE INHIBITION IS SUFFICIENT TO REDIRECT C-KIT+ CELLS TOWARD A CARDIAC FATE. EPIGENETICALLY MODIFIED C-KIT+ CELLS IMPROVED CONTRACTILE FUNCTION AND RETARDED REMODELING OF THE CONGESTIVE HEART FAILURE HEART. THIS STUDY PROVIDES NEW INSIGHTS INTO THE EFFICACY OF CARDIAC C-KIT+ CELLS IN THE ISCHEMIC HEART FAILURE MODEL.	2015	
                                                                                                                                                                                                                                                                                                                                    
4  1074  29 CLONAL HAEMATOPOIESIS IN CHRONIC ISCHAEMIC HEART FAILURE: PROGNOSTIC ROLE OF CLONE SIZE FOR DNMT3A- AND TET2-DRIVER GENE MUTATIONS. AIMS: SOMATIC MUTATIONS OF THE EPIGENETIC REGULATORS DNMT3A AND TET2 CAUSING CLONAL EXPANSION OF HAEMATOPOIETIC CELLS (CLONAL HAEMATOPOIESIS; CH) WERE SHOWN TO BE ASSOCIATED WITH POOR PROGNOSIS IN CHRONIC ISCHAEMIC HEART FAILURE (CHF). THE AIM OF OUR ANALYSIS WAS TO DEFINE A THRESHOLD OF VARIANT ALLELE FREQUENCY (VAF) FOR THE PROGNOSTIC SIGNIFICANCE OF CH IN CHF. METHODS AND RESULTS: WE ANALYSED BONE MARROW AND PERIPHERAL BLOOD-DERIVED CELLS FROM 419 PATIENTS WITH CHF BY ERROR-CORRECTED AMPLICON SEQUENCING. CUT-OFF VAFS WERE OPTIMIZED BY MAXIMIZING SENSITIVITY PLUS SPECIFICITY FROM A TIME-DEPENDENT RECEIVER OPERATING CHARACTERISTIC (ROC) CURVE ANALYSIS FROM CENSORED DATA. 56.2% OF PATIENTS WERE CARRIERS OF A DNMT3A- (N = 173) OR A TET2- (N = 113) MUTATION WITH A VAF >0.5%, WITH 59 PATIENTS HARBOURING MUTATIONS IN BOTH GENES. SURVIVAL ROC ANALYSES REVEALED AN OPTIMIZED CUT-OFF VALUE OF 0.73% FOR TET2- AND 1.15% FOR DNMT3A-CH-DRIVER MUTATIONS. FIVE-YEAR-MORTALITY WAS 18% IN PATIENTS WITHOUT ANY DETECTED DNMT3A- OR TET2 MUTATION (VAF < 0.5%), 29% WITH ONLY ONE DNMT3A- OR TET2-CH-DRIVER MUTATIONS ABOVE THE RESPECTIVE CUT-OFF LEVEL AND 42% IN PATIENTS HARBOURING BOTH DNMT3A- AND TET2-CH-DRIVER MUTATIONS ABOVE THE RESPECTIVE CUT-OFF LEVELS. IN CARRIERS OF A DNMT3A MUTATION WITH VAF >/= 1.15%, 5-YEAR MORTALITY WAS 31%, COMPARED WITH 18% MORTALITY IN THOSE WITH VAF < 1.15% (P = 0.048). LIKEWISE, IN PATIENTS WITH TET2 MUTATIONS, 5-YEAR MORTALITY WAS 32% WITH VAF >/= 0.73%, COMPARED WITH 19% MORTALITY WITH VAF < 0.73% (P = 0.029). CONCLUSION: THE PRESENT STUDY DEFINES NOVEL THRESHOLD LEVELS FOR CLONE SIZE CAUSED BY ACQUIRED SOMATIC MUTATIONS IN THE CH-DRIVER GENES DNMT3A AND TET2 THAT ARE ASSOCIATED WITH WORSE OUTCOME IN PATIENTS WITH CHF.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5  2537  29 EPIGENETICS IN HEART FAILURE PHENOTYPES. CHRONIC HEART FAILURE (HF) IS A LEADING CLINICAL AND PUBLIC PROBLEM POSING A HIGHER RISK OF MORBIDITY AND MORTALITY IN DIFFERENT POPULATIONS. HF APPEARS TO BE IN BOTH PHENOTYPIC FORMS: HF WITH REDUCED LEFT VENTRICULAR EJECTION FRACTION (HFREF) AND HF WITH PRESERVED LEFT VENTRICULAR EJECTION FRACTION (HFPEF). ALTHOUGH BOTH HF PHENOTYPES CAN BE DISTINGUISHED THROUGH CLINICAL FEATURES, CO-MORBIDITY STATUS, PREDICTION SCORE, AND TREATMENT, THE CLINICAL OUTCOMES IN PATIENTS WITH HFREF AND HFPEF ARE SIMILAR. IN THIS CONTEXT, INVESTIGATION OF VARIOUS MOLECULAR AND CELLULAR MECHANISMS LEADING TO THE DEVELOPMENT AND PROGRESSION OF BOTH HF PHENOTYPES IS VERY IMPORTANT. THERE IS EMERGING EVIDENCE THAT EPIGENETIC REGULATION MAY HAVE A CLUE IN THE PATHOGENESIS OF HF. THIS REVIEW REPRESENTS CURRENT AVAILABLE EVIDENCE REGARDING THE IMPLICATION OF EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF DIFFERENT HF PHENOTYPES AND PERSPECTIVES OF EPIGENETIC-BASED THERAPIES OF HF.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6  5068  25 PHYSICAL ACTIVITY AND PROGENITOR CELL-MEDIATED ENDOTHELIAL REPAIR IN CHRONIC HEART FAILURE: IS THERE A ROLE FOR EPIGENETICS? CHRONIC HEART FAILURE (CHF) IS THE MOST COMMON CARDIAC DISEASE AMONG THE ELDERLY AND A LEADING CAUSE OF MORTALITY IN ELDERLY PATIENTS. ENDOTHELIAL DYSFUNCTION IS HELD TO HAVE A MAJOR ROLE IN THE DEVELOPMENT AND PROGRESSION OF CHF, WHICH RESULTS IN PROGRESSIVELY IMPAIRED FUNCTIONAL CAPACITY. ENDOTHELIAL PROGENITOR CELLS (EPCS) AND CIRCULATING ANGIOGENIC CELLS (CACS) ARE THE MAIN PLAYERS INVOLVED IN THE ENDOGENOUS REPAIR MECHANISMS THAT CAN COUNTERACT ENDOTHELIAL DYSFUNCTION. A MOUNTING BODY OF DATA INDICATES THAT EXERCISE ENHANCES ENDOTHELIAL RENEWAL THROUGH MOBILIZATION OF BONE MARROW-DERIVED EPCS AND CACS, MAKING IT AN EFFECTIVE THERAPEUTIC TOOL FOR CHF. INTERESTINGLY, EMERGING EVIDENCE HAS BEEN SHOWING THAT EXERCISE TRAINING CAN ALSO PROMOTE EPIGENETIC MODIFICATIONS, E.G. DNA METHYLATION, HISTONE MODIFICATIONS, AND DIFFERENTIAL EXPRESSION OF SPECIFIC NON-CODING RNAS LIKE MICRORNA (MIRNAS). SINCE DEREGULATION OF THE MIRNAS INVOLVED IN ENDOTHELIAL FUNCTION MODULATION HAS WIDELY BEEN DOCUMENTED IN CIRCULATING CELLS AND PLASMA OF CHF PATIENTS, DEREGULATION OF EPIGENETIC FEATURES COULD PLAY A KEY ROLE IN DISEASE PROGRESSION. HERE, WE REVIEW CURRENT KNOWLEDGE OF THE CONTRIBUTION OF EPCS AND CACS TO ENDOTHELIAL REPAIR MECHANISMS IN CHF PATIENTS, FOCUSING ON THE EFFECTS INDUCED BY EXERCISE TRAINING AND HYPOTHESIZING THAT SOME OF THESE EFFECTS CAN BE MEDIATED BY EPIGENETIC MECHANISMS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
7  1778  28 EDITOR'S HIGHLIGHT: THE ALTERED DNA METHYLOME OF CHRONIC DOXORUBICIN EXPOSURE IN SPRAGUE DAWLEY RATS. DOXORUBICIN (DOX) IS A WIDELY USED TREATMENT FOR HUMAN CANCERS, BUT INCREASES THE RISK OF LIFE-THREATENING CONGESTIVE HEART FAILURE (CHF). DOX-INDUCED MITOCHONDRIAL DAMAGE IS CUMULATIVE AND PERSISTENT, SIMILAR TO THAT OBSERVED CLINICALLY FOR RISK OF CHF. RECENT EVIDENCE SUGGESTS THE PERSISTENT NATURE OF THIS INJURY IS CAUSED BY ALTERED REGULATION OF GENES IMPORTANT TO NORMAL CARDIAC FUNCTIONING. WE HYPOTHESIZE THAT CHRONIC DOX THERAPY IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS OF DNA METHYLATION STATUS, PARTICULARLY IN CRITICAL REGULATORS OF MITOCHONDRIAL FUNCTION AND CAPACITY. CARDIAC TISSUE FROM SPRAGUE DAWLEY RATS RECEIVING INJECTIONS OF DOX (2 MG/KG, S.C.) OR SALINE ONCE A WEEK FOR 6 WEEKS, FOLLOWED BY 5 WEEKS OF DRUG-FREE HOLIDAY WAS USED FOR REDUCED REPRESENTATION BISULFITE SEQUENCING TO MAP SPECIFIC SITES OF DNA METHYLATION. COMPARISON OF THESE METHYLOMES INDICATED DOX EXPOSURE ALTERS DNA METHYLATION LANDSCAPES, AND IDENTIFIED 14 GENES WITH HIGHLY ALTERED METHYLATION STATUS. PRELIMINARY FUNCTIONAL EFFECTS OF DNA METHYLATION CHANGES WERE CHARACTERIZED BY QUANTIFYING MRNA EXPRESSION OF SELECTED TARGETS (RBM20, NMNAT2, KLHL29, CACNA1C, SCN5A.) GENE EXPRESSION OF RBM20, KLHL29, AND NMNAT2 WERE SIGNIFICANTLY ALTERED IN DOX TREATED ANIMALS; KLHL29 AND NMNAT2 DEMONSTRATED SIGNIFICANT DECREASES IN PROTEIN EXPRESSION CORRESPONDING TO GENE EXPRESSION. THROUGH AN EPIGENOTYPE-TO-PHENOTYPE APPROACH, THIS STUDY IDENTIFIES POTENTIAL MARKERS AND MOLECULAR REGULATORS OF IRREVERSIBLE DOX-INDUCED CARDIOVASCULAR TOXICITY ASSOCIATED WITH CLINICALLY LIMITING CHF. HOWEVER, NONE OF THE MOST PREVALENT GENES IDENTIFIED DIRECTLY RELATE TO MITOCHONDRIAL STRUCTURE OR FUNCTION. THUS, THE INVESTIGATION FAILS TO DEMONSTRATE A DIRECT ASSOCIATION BETWEEN THIS ALTERED METHYLOME AND PERSISTENT MITOCHONDRIONOPATHY ASSOCIATED WITH CHRONIC DOXORUBICIN CARDIAC TOXICITY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8    50  35 A DEEP LEARNING MODEL FOR EARLY RISK PREDICTION OF HEART FAILURE WITH PRESERVED EJECTION FRACTION BY DNA METHYLATION PROFILES COMBINED WITH CLINICAL FEATURES. BACKGROUND: HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF), AFFECTED COLLECTIVELY BY GENETIC AND ENVIRONMENTAL FACTORS, IS THE COMMON SUBTYPE OF CHRONIC HEART FAILURE. ALTHOUGH THE AVAILABLE RISK ASSESSMENT METHODS FOR HFPEF HAVE ACHIEVED SOME PROGRESS, THEY WERE BASED ON CLINICAL OR GENETIC FEATURES ALONE. HERE, WE HAVE DEVELOPED A DEEP LEARNING FRAMEWORK, HFMERISK, USING BOTH 5 CLINICAL FEATURES AND 25 DNA METHYLATION LOCI TO PREDICT THE EARLY RISK OF HFPEF IN THE FRAMINGHAM HEART STUDY COHORT. RESULTS: THE FRAMEWORK INCORPORATES LEAST ABSOLUTE SHRINKAGE AND SELECTION OPERATOR AND EXTREME GRADIENT BOOSTING-BASED FEATURE SELECTION, AS WELL AS A FACTORIZATION-MACHINE BASED NEURAL NETWORK-BASED RECOMMENDER SYSTEM. MODEL DISCRIMINATION AND CALIBRATION WERE ASSESSED USING THE AUC AND HOSMER-LEMESHOW TEST. HFMERISK, INCLUDING 25 CPGS AND 5 CLINICAL FEATURES, HAVE ACHIEVED THE AUC OF 0.90 (95% CONFIDENCE INTERVAL 0.88-0.92) AND HOSMER-LEMESHOW STATISTIC WAS 6.17 (P = 0.632), WHICH OUTPERFORMED MODELS WITH CLINICAL CHARACTERISTICS OR DNA METHYLATION LEVELS ALONE, PUBLISHED CHRONIC HEART FAILURE RISK PREDICTION MODELS AND OTHER BENCHMARK MACHINE LEARNING MODELS. OUT OF THEM, THE DNA METHYLATION LEVELS OF TWO CPGS WERE SIGNIFICANTLY CORRELATED WITH THE PAIRED TRANSCRIPTOME LEVELS (R < -0.3, P < 0.05). BESIDES, DNA METHYLATION LOCUS IN HFMERISK WERE ASSOCIATED WITH INTERCELLULAR SIGNALING AND INTERACTION, AMINO ACID METABOLISM, TRANSPORT AND ACTIVATION AND THE CLINICAL VARIABLES WERE ALL RELATED WITH THE MECHANISM OF OCCURRENCE OF HFPEF. TOGETHER, THESE FINDINGS GIVE NEW EVIDENCE INTO THE HFMERISK MODEL. CONCLUSION: OUR STUDY PROPOSES AN EARLY RISK ASSESSMENT FRAMEWORK FOR HFPEF INTEGRATING BOTH CLINICAL AND EPIGENETIC FEATURES, PROVIDING A PROMISING PATH FOR CLINICAL DECISION MAKING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9  3064  34 GENOME-WIDE DNA METHYLATION ENCODES CARDIAC TRANSCRIPTIONAL REPROGRAMMING IN HUMAN ISCHEMIC HEART FAILURE. ISCHEMIC CARDIOMYOPATHY (ICM) IS THE CLINICAL ENDPOINT OF CORONARY HEART DISEASE AND A LEADING CAUSE OF HEART FAILURE. DESPITE GROWING DEMANDS TO DEVELOP PERSONALIZED APPROACHES TO TREAT ICM, PROGRESS IS LIMITED BY INADEQUATE KNOWLEDGE OF ITS PATHOGENESIS. SINCE EPIGENETICS HAS BEEN IMPLICATED IN THE DEVELOPMENT OF OTHER CHRONIC DISEASES, THE CURRENT STUDY WAS DESIGNED TO DETERMINE WHETHER TRANSCRIPTIONAL AND/OR EPIGENETIC CHANGES ARE SUFFICIENT TO DISTINGUISH ICM FROM OTHER ETIOLOGIES OF HEART FAILURE. SPECIFICALLY, WE HYPOTHESIZE THAT GENOME-WIDE DNA METHYLATION ENCODES TRANSCRIPTIONAL REPROGRAMMING IN ICM. RNA-SEQUENCING ANALYSIS WAS PERFORMED ON HUMAN ISCHEMIC LEFT VENTRICULAR TISSUE OBTAINED FROM PATIENTS WITH END-STAGE HEART FAILURE, WHICH ENRICHED KNOWN TARGETS OF THE POLYCOMB METHYLTRANSFERASE EZH2 COMPARED TO NON-ISCHEMIC HEARTS. COMBINED RNA SEQUENCING AND GENOME-WIDE DNA METHYLATION ANALYSIS REVEALED A ROBUST GENE EXPRESSION PATTERN CONSISTENT WITH SUPPRESSION OF OXIDATIVE METABOLISM, INDUCED ANAEROBIC GLYCOLYSIS, AND ALTERED CELLULAR REMODELING. LASTLY, KLF15 WAS IDENTIFIED AS A PUTATIVE UPSTREAM REGULATOR OF METABOLIC GENE EXPRESSION THAT WAS ITSELF REGULATED BY EZH2 IN A SET DOMAIN-DEPENDENT MANNER. OUR OBSERVATIONS THEREFORE DEFINE A NOVEL ROLE OF DNA METHYLATION IN THE METABOLIC REPROGRAMMING OF ICM. FURTHERMORE, WE IDENTIFY EZH2 AS AN EPIGENETIC REGULATOR OF KLF15 ALONG WITH DNA HYPERMETHYLATION, AND WE PROPOSE A NOVEL MECHANISM THROUGH WHICH CORONARY HEART DISEASE REPROGRAMS THE EXPRESSION OF BOTH INTERMEDIATE ENZYMES AND UPSTREAM REGULATORS OF CARDIAC METABOLISM SUCH AS KLF15.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10   353  31 ALTERED LEVELS OF IMMUNE-REGULATORY MICRORNAS IN PLASMA SAMPLES OF PATIENTS WITH LUPUS NEPHRITIS. INTRODUCTION: LUPUS NEPHRITIS (LN) IS A MAJOR CAUSE OF MORTALITY AND MORBIDITY IN THE PATIENTS WITH LUPUS, A CHRONIC AUTOIMMUNE DISEASE. THE ROLE OF GENETIC AND EPIGENETIC FACTORS IS EMPHASIZED IN THE PATHOGENESIS OF LN. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE LEVELS OF IMMUNE-REGULATORY MICRORNAS (E.G., MIR-31, MIR-125A, MIR-142-3P, MIR-146A, AND MIR-155) IN PLASMA SAMPLES OF PATIENTS WITH LN. METHODS: IN THIS STUDY, 26 PATIENTS WITH LN AND 26 HEALTHY INDIVIDUALS WERE INCLUDED. THE PLASMA LEVELS OF THE MICRORNAS WERE EVALUATED BY A QUANTITATIVE REAL-TIME PCR. MOREOVER, THE CORRELATION OF CIRCULATING PLASMA MICRORNAS WITH DISEASE ACTIVITY AND PATHOLOGICAL FINDINGS ALONG WITH THEIR ABILITY TO DISTINGUISH PATIENTS WITH LN WERE ASSESSED. RESULTS: PLASMA LEVELS OF MIR-125A (P = 0.048), MIR-146A (P = 0.005), AND MIR-155 (P< 0.001) WERE SIGNIFICANTLY HIGHER IN COMPARISON BETWEEN THE CASES AND CONTROLS. THE PLASMA LEVEL OF MIR-146A SIGNIFICANTLY CORRELATED WITH THE LEVEL OF ANTI-DOUBLE STRAND-DNA ANTIBODY AND PROTEINURIA. MOREOVER, THERE WAS A SIGNIFICANT CORRELATION BETWEEN MIR-142-3P LEVELS AND DISEASE CHRONICITY AND ACTIVITY INDEX (P <0.05). THE MULTIVARIATE ROC CURVE ANALYSIS INDICATED THE PLASMA CIRCULATING MIR-125A, MIR-142-3P, MIR-146, AND MIR-155 TOGETHER COULD DISCRIMINATE MOST OF THE PATIENTS WITH LN FROM CONTROLS WITH AREA AN UNDER CURVE (AUC) OF 0.89 [95% CI, 0.80-0.98, P<0.001], 88% SENSITIVITY, AND 78% SPECIFICITY. CONCLUSION: BASED ON THE FINDINGS OF THE PRESENT STUDY, THE STUDIED MICRORNAS MAY BE INVOLVED IN THE PATHOGENESIS AND DEVELOPMENT OF LN AND HAVE THE POTENTIAL TO BE USED AS DIAGNOSTIC AND THERAPEUTIC MARKERS IN LN.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  4573  20 MYOCARDIAL INFARCTION-ASSOCIATED TRANSCRIPT, A LONG NONCODING RNA, IS OVEREXPRESSED DURING DILATED CARDIOMYOPATHY DUE TO CHRONIC CHAGAS DISEASE. LONG NONCODING RNAS (LNCRNAS) MODULATE GENE EXPRESSION AT THE EPIGENETIC, TRANSCRIPTIONAL, AND POSTTRANSCRIPTIONAL LEVELS. DYSREGULATION OF THE LNCRNA KNOWN AS MYOCARDIAL INFARCTION-ASSOCIATED TRANSCRIPT (MIAT) HAS BEEN ASSOCIATED WITH MYOCARDIAL INFARCTION. CHAGAS DISEASE CAUSES A SEVERE INFLAMMATORY DILATED CHRONIC CARDIOMYOPATHY (CCC). WE INVESTIGATED THE ROLE OF MIAT IN CCC. A WHOLE-TRANSCRIPTOME ANALYSIS OF HEART BIOPSY SPECIMENS AND FORMALIN-FIXED, PARAFFIN-EMBEDDED SAMPLES REVEALED THAT MIAT WAS OVEREXPRESSED IN PATIENTS WITH CCC, COMPARED WITH SUBJECTS WITH NONINFLAMMATORY DILATED CARDIOMYOPATHY AND CONTROLS. THESE RESULTS WERE CONFIRMED IN A MOUSE MODEL. RESULTS SUGGEST THAT MIAT IS A SPECIFIC BIOMARKER OF CCC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12  3489  23 IDENTIFICATION OF EPIGENETIC INTERACTIONS BETWEEN MICRORNA-30C-5P AND DNA METHYLTRANSFERASES IN NEUROPATHIC PAIN. NEUROPATHIC PAIN IS A PREVALENT AND SEVERE CHRONIC SYNDROME, OFTEN REFRACTORY TO TREATMENT, WHOSE DEVELOPMENT AND MAINTENANCE MAY INVOLVE EPIGENETIC MECHANISMS. WE PREVIOUSLY DEMONSTRATED A CAUSAL RELATIONSHIP BETWEEN MIR-30C-5P UPREGULATION IN NOCICEPTION-RELATED NEURAL STRUCTURES AND NEUROPATHIC PAIN IN RATS SUBJECTED TO SCIATIC NERVE INJURY. FURTHERMORE, A SHORT COURSE OF AN MIR-30C-5P INHIBITOR ADMINISTERED INTO THE CISTERNA MAGNA EXERTS LONG-LASTING ANTIALLODYNIC EFFECTS VIA A TGF-BETA1-MEDIATED MECHANISM. HEREIN, WE SHOW THAT MIR-30C-5P INHIBITION LEADS TO GLOBAL DNA HYPER-METHYLATION OF NEURONS IN THE LUMBAR DORSAL ROOT GANGLIA AND SPINAL DORSAL HORN IN RATS SUBJECTED TO SCIATIC NERVE INJURY. SPECIFICALLY, THE INHIBITION OF MIR-30-5P SIGNIFICANTLY INCREASED THE EXPRESSION OF THE NOVO DNA METHYLTRANSFERASES DNMT3A AND DNMT3B IN THOSE STRUCTURES. FURTHERMORE, WE IDENTIFIED THE MECHANISM AND FOUND THAT MIR-30C-5P TARGETS THE MRNAS OF DNMT3A AND DNMT3B. QUANTITATIVE METHYLATION ANALYSIS REVEALED THAT THE PROMOTER REGION OF THE ANTIALLODYNIC CYTOKINE TGF-BETA1 WAS HYPOMETHYLATED IN THE SPINAL DORSAL HORN OF NERVE-INJURED RATS TREATED WITH THE MIR-30C-5P INHIBITOR, WHILE THE PROMOTER OF NFYC, THE HOST GENE OF MIR-30C-5P, WAS HYPERMETHYLATED. THESE RESULTS ARE CONSISTENT WITH LONG-TERM PROTECTION AGAINST NEUROPATHIC PAIN DEVELOPMENT AFTER NERVE INJURY. ALTOGETHER, OUR RESULTS HIGHLIGHT THE KEY ROLE OF MIR-30C-5P IN THE EPIGENETIC MECHANISMS' UNDERLYING NEUROPATHIC PAIN AND PROVIDE THE BASIS FOR MIR-30C-5P AS A THERAPEUTIC TARGET.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  1785  24 EFFECT OF APABETALONE ON CARDIOVASCULAR EVENTS IN DIABETES, CKD, AND RECENT ACUTE CORONARY SYNDROME: RESULTS FROM THE BETONMACE RANDOMIZED CONTROLLED TRIAL. BACKGROUND AND OBJECTIVES: CKD AND TYPE 2 DIABETES MELLITUS INTERACT TO INCREASE THE RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (I.E., CARDIOVASCULAR DEATH, NONFATAL MYOCARDIAL INFARCTION, OR STROKE) AND CONGESTIVE HEART FAILURE. A MALADAPTIVE EPIGENETIC RESPONSE MAY BE A CARDIOVASCULAR RISK DRIVER AND AMENABLE TO MODIFICATION WITH APABETALONE, A SELECTIVE MODULATOR OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN TRANSCRIPTION SYSTEM. WE EXAMINED THIS QUESTION IN A PRESPECIFIED ANALYSIS OF BETONMACE, A PHASE 3 TRIAL. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BETONMACE WAS AN EVENT-DRIVEN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING EFFECTS OF APABETALONE VERSUS PLACEBO ON MAJOR ADVERSE CARDIOVASCULAR EVENTS AND HEART FAILURE HOSPITALIZATIONS IN 2425 PARTICIPANTS WITH TYPE 2 DIABETES AND A RECENT ACUTE CORONARY SYNDROME, INCLUDING 288 PARTICIPANTS WITH CKD WITH EGFR <60 ML/MIN PER 1.73 M(2) AT BASELINE. THE PRIMARY END POINT IN BETONMACE WAS THE TIME TO THE FIRST MAJOR ADVERSE CARDIOVASCULAR EVENT, WITH A SECONDARY END POINT OF TIME TO HOSPITALIZATION FOR HEART FAILURE. RESULTS: MEDIAN FOLLOW-UP WAS 27 MONTHS (INTERQUARTILE RANGE, 20-32 MONTHS). IN PARTICIPANTS WITH CKD, APABETALONE COMPARED WITH PLACEBO WAS ASSOCIATED WITH FEWER MAJOR ADVERSE CARDIOVASCULAR EVENTS (13 EVENTS IN 124 PATIENTS [11%] VERSUS 35 EVENTS IN 164 PATIENTS [21%]; HAZARD RATIO, 0.50; 95% CONFIDENCE INTERVAL, 0.26 TO 0.96) AND FEWER HEART FAILURE-RELATED HOSPITALIZATIONS (THREE HOSPITALIZATIONS IN 124 PATIENTS [3%] VERSUS 14 HOSPITALIZATIONS IN 164 PATIENTS [9%]; HAZARD RATIO, 0.48; 95% CONFIDENCE INTERVAL, 0.26 TO 0.86). IN THE NON-CKD GROUP, THE CORRESPONDING HAZARD RATIO VALUES WERE 0.96 (95% CONFIDENCE INTERVAL, 0.74 TO 1.24) FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND 0.76 (95% CONFIDENCE INTERVAL, 0.46 TO 1.27) FOR HEART FAILURE-RELATED HOSPITALIZATION. INTERACTION OF CKD ON TREATMENT EFFECT WAS P=0.03 FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND P=0.12 FOR HEART FAILURE-RELATED HOSPITALIZATION. PARTICIPANTS WITH CKD SHOWED SIMILAR NUMBERS OF ADVERSE EVENTS, REGARDLESS OF RANDOMIZATION TO APABETALONE OR PLACEBO (119 [73%] VERSUS 88 [71%] PATIENTS), AND THERE WERE FEWER SERIOUS ADVERSE EVENTS (29% VERSUS 43%; P=0.02) IN THE APABETALONE GROUP. CONCLUSIONS: APABETALONE MAY REDUCE THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH CKD AND TYPE 2 DIABETES WHO HAVE A HIGH BURDEN OF CARDIOVASCULAR DISEASE.	2021	

14   749  27 CARDIAC EPIGENETIC CHANGES IN VEGF SIGNALING GENES ASSOCIATE WITH MYOCARDIAL MICROVASCULAR RAREFACTION IN EXPERIMENTAL CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS COMMON IN PATIENTS WITH HEART FAILURE AND OFTEN RESULTS IN LEFT VENTRICULAR DIASTOLIC DYSFUNCTION (LVDD). HOWEVER, THE MECHANISMS RESPONSIBLE FOR CARDIAC DAMAGE IN CKD-LVDD REMAIN TO BE ELUCIDATED. EPIGENETIC ALTERATIONS MAY IMPOSE LONG-LASTING EFFECTS ON CELLULAR TRANSCRIPTION AND FUNCTION, BUT THEIR EXACT ROLE IN CKD-LVDD IS UNKNOWN. WE INVESTIGATE WHETHER CHANGES IN CARDIAC SITE-SPECIFIC DNA METHYLATION PROFILES MIGHT BE IMPLICATED IN CARDIAC ABNORMALITIES IN CKD-LVDD. CKD-LVDD AND NORMAL CONTROL PIGS (N = 6 EACH) WERE STUDIED FOR 14 WK. RENAL AND CARDIAC HEMODYNAMICS WERE QUANTIFIED BY MULTIDETECTOR CT AND ECHOCARDIOGRAPHY. IN RANDOMLY SELECTED PIGS (N = 3/GROUP), CARDIAC SITE-SPECIFIC 5-METHYLCYTOSINE (5MC) IMMUNOPRECIPITATION (MEDIP)- AND MRNA-SEQUENCING (SEQ) WERE PERFORMED, FOLLOWED BY INTEGRATED (MEDIP-SEQ/MRNA-SEQ ANALYSIS), AND CONFIRMATORY EX VIVO STUDIES. MEDIP-SEQ ANALYSIS REVEALED 261 GENES WITH HIGHER (FOLD CHANGE > 1.4; P < 0.05) AND 162 GENES WITH LOWER (FOLD CHANGE < 0.7; P < 0.05) 5MC LEVELS IN CKD-LVDD VERSUS NORMAL PIGS, WHICH WERE PRIMARILY IMPLICATED IN VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)-RELATED SIGNALING AND ANGIOGENESIS. INTEGRATED MEDIP-SEQ/MRNA-SEQ ANALYSIS IDENTIFIED A SELECT GROUP OF VEGF-RELATED GENES IN WHICH 5MC LEVELS WERE HIGHER, BUT MRNA EXPRESSION WAS LOWER IN CKD-LVDD VERSUS NORMAL PIGS. CARDIAC VEGF SIGNALING GENE AND VEGF PROTEIN EXPRESSION WERE BLUNTED IN CKD-LVDD COMPARED WITH CONTROLS AND WERE ASSOCIATED WITH DECREASED SUBENDOCARDIAL MICROVASCULAR DENSITY. CARDIAC EPIGENETIC CHANGES IN VEGF-RELATED GENES ARE ASSOCIATED WITH IMPAIRED ANGIOGENESIS AND CARDIAC MICROVASCULAR RAREFACTION IN SWINE CKD-LVDD. THESE OBSERVATIONS MAY ASSIST IN DEVELOPING NOVEL THERAPIES TO AMELIORATE CARDIAC DAMAGE IN CKD-LVDD.NEW & NOTEWORTHY CHRONIC KIDNEY DISEASE (CKD) OFTEN LEADS TO LEFT VENTRICULAR DIASTOLIC DYSFUNCTION (LVDD) AND HEART FAILURE. USING A NOVEL TRANSLATIONAL SWINE MODEL OF CKD-LVDD, WE CHARACTERIZE THE CARDIAC EPIGENETIC LANDSCAPE, IDENTIFYING SITE-SPECIFIC 5-METHYLCYTOSINE CHANGES IN VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)-RELATED GENES ASSOCIATED WITH IMPAIRED ANGIOGENESIS AND CARDIAC MICROVASCULAR RAREFACTION. THESE OBSERVATIONS SHED LIGHT ON THE MECHANISMS OF CARDIAC MICROVASCULAR DAMAGE IN CKD-LVDD AND MAY ASSIST IN DEVELOPING NOVEL THERAPIES FOR THESE PATIENTS.	2023	
                                                                                       
15  5985  27 TET2-MEDIATED CLONAL HEMATOPOIESIS ACCELERATES HEART FAILURE THROUGH A MECHANISM INVOLVING THE IL-1BETA/NLRP3 INFLAMMASOME. BACKGROUND: RECENT STUDIES HAVE SHOWN THAT HEMATOPOIETIC STEM CELLS CAN UNDERGO CLONAL EXPANSION SECONDARY TO SOMATIC MUTATIONS IN LEUKEMIA-RELATED GENES, THUS LEADING TO AN AGE-DEPENDENT ACCUMULATION OF MUTANT LEUKOCYTES IN THE BLOOD. THIS SOMATIC MUTATION-RELATED CLONAL HEMATOPOIESIS IS COMMON IN HEALTHY OLDER INDIVIDUALS, BUT IT HAS BEEN ASSOCIATED WITH AN INCREASED INCIDENCE OF FUTURE CARDIOVASCULAR DISEASE. THE EPIGENETIC REGULATOR TET2 IS FREQUENTLY MUTATED IN BLOOD CELLS OF INDIVIDUALS EXHIBITING CLONAL HEMATOPOIESIS. OBJECTIVES: THIS STUDY INVESTIGATED WHETHER TET2 MUTATIONS WITHIN HEMATOPOIETIC CELLS CAN CONTRIBUTE TO HEART FAILURE IN 2 MODELS OF CARDIAC INJURY. METHODS: HEART FAILURE WAS INDUCED IN MICE BY PRESSURE OVERLOAD, ACHIEVED BY TRANSVERSE AORTIC CONSTRICTION OR CHRONIC ISCHEMIA INDUCED BY THE PERMANENT LIGATION OF THE LEFT ANTERIOR DESCENDING ARTERY. COMPETITIVE BONE MARROW TRANSPLANTATION STRATEGIES WITH TET2-DEFICIENT CELLS WERE USED TO MIMIC TET2 MUTATION-DRIVEN CLONAL HEMATOPOIESIS. ALTERNATIVELY, TET2 WAS SPECIFICALLY ABLATED IN MYELOID CELLS USING CRE RECOMBINASE EXPRESSED FROM THE LYSM PROMOTER. RESULTS: IN BOTH EXPERIMENTAL HEART FAILURE MODELS, HEMATOPOIETIC OR MYELOID TET2 DEFICIENCY WORSENED CARDIAC REMODELING AND FUNCTION, IN PARALLEL WITH INCREASED INTERLEUKIN-1BETA (IL-1BETA) EXPRESSION. TREATMENT WITH A SELECTIVE NLRP3 INFLAMMASOME INHIBITOR PROTECTED AGAINST THE DEVELOPMENT OF HEART FAILURE AND ELIMINATED THE DIFFERENCES IN CARDIAC PARAMETERS BETWEEN TET2-DEFICIENT AND WILD-TYPE MICE. CONCLUSIONS: TET2 DEFICIENCY IN HEMATOPOIETIC CELLS IS ASSOCIATED WITH GREATER CARDIAC DYSFUNCTION IN MURINE MODELS OF HEART FAILURE AS A RESULT OF ELEVATED IL-1BETA SIGNALING. THESE DATA SUGGEST THAT INDIVIDUALS WITH TET2-MEDIATED CLONAL HEMATOPOIESIS MAY BE AT GREATER RISK OF DEVELOPING HEART FAILURE AND RESPOND BETTER TO IL-1BETA-NLRP3 INFLAMMASOME INHIBITION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  3719  22 INHIBITION OF BET PROTEINS REDUCES RIGHT VENTRICLE HYPERTROPHY AND PULMONARY HYPERTENSION RESULTING FROM COMBINED HYPOXIA AND PULMONARY INFLAMMATION. PULMONARY HYPERTENSION IS A CO-MORBIDITY, WHICH STRONGLY PARTICIPATES IN MORBI-MORTALITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). RECENT FINDINGS SHOWED THAT BROMODOMAIN-CONTAINING PROTEINS, IN CHARGE OF READING HISTONE ACETYLATION, COULD BE INVOLVED IN PULMONARY ARTERIAL HYPERTENSION. OUR AIM WAS TO STUDY THE EFFECT OF I-BET151, AN INHIBITOR OF BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET), ON THE RIGHT VENTRICLE HYPERTROPHY AND PULMONARY HYPERTENSION, INDUCED BY A COMBINATION OF CHRONIC HYPOXIA AND PULMONARY INFLAMMATION, AS THE TWO MAIN STIMULI ENCOUNTERED IN COPD. ADULT WISTAR MALE RATS, EXPOSED TO CHRONIC HYPOXIA PLUS PULMONARY INFLAMMATION (CHPI), SHOWED A SIGNIFICANT RIGHT VENTRICLE HYPERTROPHY (+57%, P < 0.001), AN INCREASE IN SYSTOLIC PRESSURE (+46%, P < 0.001) AND IN CONTRACTION SPEED (+36%, P < 0.001), WHEN COMPARED TO CONTROL ANIMALS. I-BET151 TREATED ANIMALS (CHPI-IB) SHOWED RESTORED HEMODYNAMIC PARAMETERS TO LEVELS SIMILAR TO CONTROL ANIMALS, DESPITE CHRONIC HYPOXIA PLUS EXPOSURE TO PULMONARY INFLAMMATION. THEY DISPLAYED LOWER RIGHT VENTRICLE HYPERTROPHY AND HEMATOCRIT COMPARED TO THE CHPI GROUP (RESPECTIVELY -16%, P < 0.001; AND -9%, P < 0.05). OUR DESCRIPTIVE STUDY SHOWS A VALUABLE EFFECT OF THE INHIBITION OF BROMODOMAIN AND EXTRA-TERMINAL DOMAIN PROTEINS ON HEMODYNAMIC PARAMETERS, DESPITE THE PRESENCE OF CHRONIC HYPOXIA AND PULMONARY INFLAMMATION. THIS SUGGESTS THAT SUCH INHIBITION COULD BE OF POTENTIAL INTEREST FOR COPD PATIENTS WITH PULMONARY HYPERTENSION. FURTHER STUDIES ARE NEEDED TO UNRAVEL THE UNDERLYING MECHANISMS INVOLVED AND THE NET BENEFITS OF INHIBITING ADAPTATIONS TO CHRONIC HYPOXIA.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
17   245  24 ADRENERGIC REPRESSION OF THE EPIGENETIC READER MECP2 FACILITATES CARDIAC ADAPTATION IN CHRONIC HEART FAILURE. RATIONALE: IN CHRONIC HEART FAILURE, INCREASED ADRENERGIC ACTIVATION CONTRIBUTES TO STRUCTURAL REMODELING AND ALTERED GENE EXPRESSION. ALTHOUGH ADRENERGIC SIGNALING ALTERS HISTONE MODIFICATIONS, IT IS UNKNOWN, WHETHER IT ALSO AFFECTS OTHER EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION AND ITS RECOGNITION. OBJECTIVE: THE AIM OF THIS STUDY WAS TO IDENTIFY THE MECHANISM OF REGULATION OF THE METHYL-CPG-BINDING PROTEIN 2 (MECP2) AND ITS FUNCTIONAL SIGNIFICANCE DURING CARDIAC PRESSURE OVERLOAD AND UNLOADING. METHODS AND RESULTS: MECP2 WAS IDENTIFIED AS A REVERSIBLY REPRESSED GENE IN MOUSE HEARTS AFTER TRANSVERSE AORTIC CONSTRICTION AND WAS NORMALIZED AFTER REMOVAL OF THE CONSTRICTION. SIMILARLY, MECP2 REPRESSION IN HUMAN FAILING HEARTS RESOLVED AFTER UNLOADING BY A LEFT VENTRICULAR ASSIST DEVICE. THE CLUSTER MIR-212/132 WAS UPREGULATED AFTER TRANSVERSE AORTIC CONSTRICTION OR ON ACTIVATION OF ALPHA1- AND BETA1-ADRENOCEPTORS AND MIR-212/132 LED TO REPRESSION OF MECP2. PREVENTION OF MECP2 REPRESSION BY A CARDIOMYOCYTE-SPECIFIC, DOXYCYCLINE-REGULATABLE TRANSGENIC MOUSE MODEL AGGRAVATED CARDIAC HYPERTROPHY, FIBROSIS, AND CONTRACTILE DYSFUNCTION AFTER TRANSVERSE AORTIC CONSTRICTION. ABLATION OF MECP2 IN CARDIOMYOCYTES FACILITATED RECOVERY OF FAILING HEARTS AFTER REVERSIBLE TRANSVERSE AORTIC CONSTRICTION. GENOME-WIDE EXPRESSION ANALYSIS, CHROMATIN IMMUNOPRECIPITATION EXPERIMENTS, AND DNA METHYLATION ANALYSIS IDENTIFIED MITOCHONDRIAL GENES AND THEIR TRANSCRIPTIONAL REGULATORS AS MECP2 TARGET GENES. COINCIDENT WITH ITS REPRESSION, MECP2 WAS REMOVED FROM ITS TARGET GENES, WHEREAS DNA METHYLATION OF MECP2 TARGET GENES REMAINED STABLE DURING PRESSURE OVERLOAD. CONCLUSIONS: THESE DATA CONNECT ADRENERGIC ACTIVATION WITH A MICRORNA-MECP2 EPIGENETIC PATHWAY THAT IS IMPORTANT FOR CARDIAC ADAPTATION DURING THE DEVELOPMENT AND RECOVERY FROM HEART FAILURE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
18  3592  24 IMPAIRED VASCULAR FUNCTION CONTRIBUTES TO EXERCISE INTOLERANCE IN CHRONIC KIDNEY DISEASE. BACKGROUND: EXERCISE INTOLERANCE IS AN IMPORTANT FEATURE IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) AND IS PROGNOSTIC FOR BOTH INCREASED MORBIDITY AND MORTALITY. LITTLE IS KNOWN ABOUT THE UNDERLYING MECHANISMS IN PREDIALYSIS CKD. THIS STUDY AIMED TO GAIN MORE INSIGHT INTO THE ROLE OF VASCULAR DYSFUNCTION IN THE EXERCISE INTOLERANCE OF PREDIALYSIS CKD. IN ADDITION, VASCULAR-RELATED MICRORNAS (MIRNAS)-AS EPIGENETIC REGULATORS OF EXERCISE CAPACITY-WERE ANALYSED. METHODS: SIXTY-THREE PATIENTS WITH CKD STAGES 1-5 AND 18 HEALTHY CONTROLS WERE INCLUDED. PEAK OXYGEN CONSUMPTION (VO(2)PEAK) WAS DETERMINED BY CARDIOPULMONARY EXERCISE TESTING, ENDOTHELIAL FUNCTION BY FLOW-MEDIATED DILATION (FMD) AND ARTERIAL STIFFNESS BY CAROTID-FEMORAL PULSE WAVE VELOCITY (PWV). PLASMA MIRNA LEVELS (MIR-21, MIR-126, MIR-146A, MIR-150 AND MIR-210) WERE QUANTIFIED BY QUANTITATIVE RT-PCR. RESULTS: VO(2)PEAK WAS ALREADY IMPAIRED IN MILD CKD (STAGES 1-3A) AND SIGNIFICANTLY CORRELATED WITH ESTIMATED GLOMERULAR FILTRATION RATE (EGFR; R = 0.525, P < 0.001). LIKEWISE, BOTH FMD AND PWV WERE SIGNIFICANTLY CORRELATED WITH EGFR (R = 0.319, P = 0.007 AND R = -0.365, P = 0.001, RESPECTIVELY). IN MULTIPLE REGRESSION ANALYSIS, PWV REMAINED ONE OF THE STRONGEST INDEPENDENT DETERMINANTS OF VO(2)PEAK (BETA = -0.301, P = 0.01). OF THE STUDIED MIRNA, CIRCULATING LEVELS OF MIR-146A AND MIR-150 CORRELATED WITH EGFR, PWV AND VO(2)PEAK, BUT THE ASSOCIATION WITH THE LATTER WAS LOST WHEN CORRECTING FOR PWV. CONCLUSIONS: ARTERIAL STIFFNESS CONTRIBUTES TO THE OBSERVED REDUCED AEROBIC CAPACITY IN PREDIALYSIS CKD, INDEPENDENT OF AGE, HAEMOGLOBIN LEVELS AND ENDOTHELIAL FUNCTION AND REPRESENTS A PROMISING THERAPEUTIC TARGET FOR IMPROVING EXERCISE CAPACITY IN THIS POPULATION. FUTURE WORK IS REQUIRED TO ELUCIDATE WHY HIGHER CIRCULATING LEVELS OF MIR-146A AND MIR-150 ARE ASSOCIATED WITH IMPAIRED RENAL FUNCTION AND INCREASED ARTERIAL STIFFNESS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19  3722  25 INHIBITION OF DNA METHYLATION DURING CHRONIC OBSTRUCTIVE BLADDER DISEASE (COBD) IMPROVES FUNCTION, PATHOLOGY AND EXPRESSION. PARTIAL BLADDER OUTLET OBSTRUCTION DUE TO PROSTATE HYPERPLASIA OR POSTERIOR URETHRAL VALVES, IS A WIDESPREAD CAUSE OF URINARY DYSFUNCTION, PATIENT DISCOMFORT AND ALSO RESPONSIBLE FOR IMMENSE HEALTH CARE COSTS. EVEN AFTER REMOVAL OR RELIEF OF OBSTRUCTION, THE FUNCTIONAL AND PATHOLOGIC ASPECTS OF OBSTRUCTION REMAIN AS A CHRONIC OBSTRUCTIVE BLADDER DISEASE (COBD). EPIGENETIC CHANGES, SUCH AS DNA METHYLATION, CONTRIBUTE TO THE PERSISTENT CHARACTER OF MANY CHRONIC DISEASES, AND MAY BE ALTERED IN COBD. WE TESTED WHETHER CANDIDATE GENES AND PATHWAYS AND THE PATHOPHYSIOLOGY OF COBD WERE AFFECTED BY A HYPOMETHYLATING AGENT, DECITABINE (DAC). COBD WAS CREATED IN FEMALE SPRAGUE-DAWLEY RATS BY SURGICAL LIGATION OF THE URETHRA FOR 6 WEEKS, FOLLOWED BY REMOVAL OF THE SUTURE. SHAM LIGATIONS WERE PERFORMED BY PASSING THE SUTURE BEHIND THE URETHRA. AFTER REMOVAL OF THE OBSTRUCTION OR SHAM REMOVAL, ANIMALS WERE RANDOMIZED TO DAC TREATMENT (1 MG/KG/3-TIMES/WEEK INTRAPERITONEALLY) OR VEHICLE (NORMAL SALINE). BLADDER FUNCTION WAS NON-INVASIVELY TESTED USING METABOLIC CAGES, BOTH ONE DAY PRIOR TO DE-OBSTRUCTION AT 6 WEEKS AND PRIOR TO SACRIFICE AT 10 WEEKS. RESIDUAL VOLUME AND BLADDER MASS WERE MEASURED FOR EACH BLADDER. BLADDERS WERE EXAMINED BY IMMUNOSTAINING AS WELL AS QPCR. THE EFFECTS OF DNA METHYLTRANSFERASE (DNMT)-3A KNOCKOUT OR OVEREXPRESSION ON SMOOTH MUSCLE CELL (SMC) FUNCTION AND PHENOTYPE WERE ALSO EXAMINED IN BLADDER SMC AND EX VIVO CULTURE. RESIDUAL VOLUMES OF THE DAC TREATED GROUP WERE NOT SIGNIFICANTLY DIFFERENT FROM THE NS GROUP. COMPARED TO COBD NS, COBD DAC TREATMENT HELPED PRESERVE MICTURITION VOLUME WITH A SIGNIFICANT RECOVERY OF THE VOIDING EFFICIENCY (RATIO OF THE MAXIMUM VOIDED VOLUME/MAXIMUM BLADDER CAPACITY) BY ONE THIRD (FIG. 1, P > 0.05). BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) VARIANTS 1 AND 5 WERE UPREGULATED BY COBD AND SIGNIFICANTLY REDUCED BY DAC TREATMENT. DEPOSITION OF COLLAGEN IN THE COBD BLADDER WAS REDUCED BY DAC, BUT GROSS HYPERTROPHY REMAINED. IN BLADDER SMC, DNMT3A OVEREXPRESSION LED TO A LOSS OF CONTRACTILE FUNCTION AND PHENOTYPE. IN BLADDERS, PERSISTENTLY ALTERED BY COBD, INHIBITION OF DNA-METHYLATION ENHANCES FUNCTIONAL RECOVERY, UNLIKE TREATMENT DURING PARTIAL OBSTRUCTION, WHICH EXACERBATES OBSTRUCTIVE PATHOLOGY. THE UNDERLYING MECHANISMS MAY RELATE TO THE GENE EXPRESSION CHANGES IN BDNF AND THEIR EFFECTS ON SIGNALING IN THE BLADDER.	2021	
                                                                                          
20  6368  34 THE ROLE OF MICRORNAS IN CHRONIC PSEUDOMONAS LUNG INFECTION IN CYSTIC FIBROSIS. BACKGROUND: CYSTIC FIBROSIS (CF) IS THE MOST COMMON LIFE LIMITING GENETIC DISORDER, CHARACTERIZED BY CHRONIC RESPIRATORY FAILURE SECONDARY TO INFLAMMATION AND CHRONIC BACTERIAL LUNG INFECTION. PSEUDOMONAS AERUGINOSA LUNG INFECTION IS ASSOCIATED WITH MORE SEVERE LUNG DISEASE AND RAPID PROGRESSION OF RESPIRATORY FAILURE WHEN COMPARED TO STAPHYLOCOCCUS AUREUS INFECTION. WE HYPOTHESIZED THAT A SPECIFIC SIGNATURE OF EPIGENETIC FACTORS TARGETING SPECIFIC GENE TRANSCRIPTS CONTRIBUTES TO THE INCREASED MORBIDITY SEEN IN CF PATIENTS WITH CHRONIC PSEUDOMONAS INFECTION. METHODS: WE COLLECTED EXHALED BREATH CONDENSATE (EBC) FROM 27 SUBJECTS AND EVALUATED MIRNA SIGNATURES IN THESE SAMPLES USING COMMERCIAL PCR ARRAY. WE IDENTIFIED PREDICTED MRNA TARGETS AND ASSOCIATED SIGNALING PATHWAYS USING INGENUITY PATHWAY ANALYSIS. RESULTS: WE FOUND 11 DIFFERENTIALLY EXPRESSED MIRNAS IN EBC OF PATIENTS INFECTED WITH PSEUDOMONAS AERUGINOSA COMPARED TO EBC FROM CF PATIENTS WHO WERE NOT CHRONICALLY INFECTED WITH PSEUDOMONAS AERUGINOSA (P < 0.05). SIX OF THESE MIRNAS (HSA-MIRNA-1247, HSA-MIRNA-1276, HSA-MIRNA-449C, HSA-MIRNA-3170, HSA-MIRNA-432-5P AND HSA-MIR-548) WERE SIGNIFICANTLY DIFFERENT IN THE CF PSEUDOMONAS POSITIVE GROUP WHEN COMPARED TO BOTH THE CF PSEUDOMONAS NEGATIVE GROUP AND HEALTHY CONTROL GROUP. INGENUITY PATHWAY ANALYSIS (IPA) REVEALED ORGANISMAL INJURY AND ABNORMALITIES, REPRODUCTIVE SYSTEM DISEASE AND CANCER AS THE TOP DISEASES AND BIO FUNCTIONS ASSOCIATED WITH THESE MIRNAS. IPA ALSO DETECTED RELA, JUN, TNF, IL-10, CTNNB1, IL-13, SERPINB8, CALM1, STARD3NL, SFI1, CD55, RPS6KA4, TTC36 AND HIST1H3D AS THE TOP TARGET GENES FOR THESE MIRNAS. CONCLUSION: OUR STUDY IDENTIFIED 6 MIRNAS AS EPIGENETIC FACTORS SPECIFICALLY ASSOCIATED WITH CHRONIC PSEUDOMONAS INFECTION IN PATIENTS WITH CF.	2019