1  6569 152 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	
                                                                                                                                                                                                                                                                            
2  5532  33 RODENT MODELS OF GROUP 1 PULMONARY HYPERTENSION. WORLD HEALTH ORGANIZATION CATEGORY 1 PULMONARY HYPERTENSION (PH) IS A HETEROGENEOUS SYNDROME IN WHICH PH ORIGINATES IN THE SMALL PULMONARY ARTERIES AND IS THEREFORE ALSO REFERRED TO AS PULMONARY ARTERIAL HYPERTENSION (PAH). COMMON PATHOPHYSIOLOGIC FEATURES INCLUDE ENDOTHELIAL DYSFUNCTION, EXCESSIVE PROLIFERATION AND IMPAIRED APOPTOSIS OF VASCULAR CELLS, AND MITOCHONDRIAL FRAGMENTATION. THE PROLIFERATION/APOPTOSIS IMBALANCE RELATES IN PART TO ACTIVATION OF THE TRANSCRIPTION FACTORS HYPOXIA-INDUCIBLE FACTOR-1ALPHA (HIF-1ALPHA) AND NUCLEAR FACTOR OF ACTIVATED T-CELLS (NFAT) AND APOPTOSIS REPRESSORS, SUCH AS SURVIVIN. PERIVASCULAR INFLAMMATION, DISRUPTION OF ADVENTITIAL CONNECTIVE TISSUE, AND A GLYCOLYTIC METABOLIC SHIFT IN VASCULAR CELLS AND RIGHT VENTRICULAR MYOCYTES ALSO OCCUR IN PAH. THERE ARE IMPORTANT GENETIC AND EPIGENETIC PREDISPOSITIONS TO PAH. THIS REVIEW ASSESSES THE FIDELITY OF EXISTING ANIMAL MODELS TO HUMAN PAH. NO SINGLE MODEL CAN PERFECTLY RECAPITULATE THE MANY DIVERSE FORMS OF PH IN CATEGORY 1; HOWEVER, ACCEPTABLE MODELS EXIST. PAH INDUCED BY MONOCROTALINE AND CHRONIC HYPOXIA PLUS SU-5416 (CH+SU) IN RATS DISPLAY ENDOTHELIAL DYSFUNCTION, PROLIFERATION/APOPTOSIS IMBALANCE, AND DEVELOP THE GLYCOLYTIC METABOLIC PROFILE OF HUMAN PAH. HISTOLOGICALLY, CH+SU BEST CONFORMS TO PAH IN THAT IT DEVELOPS COMPLEX VASCULAR LESIONS, INCLUDING PLEXIFORM LESIONS. HOWEVER, THE MONOCROTALINE MODEL CAN BE INDUCED TO MANIFEST COMPLEX VASCULAR LESIONS AND DOES MANIFEST THE TENDENCY OF PAH PATIENTS TO DIE OF RIGHT VENTRICULAR (RV) FAILURE. MURINE MODELS OFFER GREATER MOLECULAR CERTAINTY THAN RAT MODELS BUT RARELY DEVELOP SIGNIFICANT PH, HAVE LESS RIGHT VENTRICULAR HYPERTROPHY (RVH) AND PULMONARY ARTERY (PA) REMODELING, AND ARE HARDER TO IMAGE AND CATHETERIZE. THE USE OF HIGH FIDELITY CATHETERIZATION AND ADVANCED IMAGING (MICROPET-CT, HIGH FREQUENCY ECHOCARDIOGRAPHY, HIGH FIELD STRENGTH MRI) AND FUNCTIONAL TESTING (TREADMILL) PERMIT ACCURATE PHENOTYPING OF EXPERIMENTAL MODELS OF PAH. PRECLINICAL TRIAL DESIGN IS AN IMPORTANT ASPECT OF TESTING EXPERIMENTAL PAH THERAPIES. THE USE OF MULTIPLE COMPLEMENTARY MODELS WITH ADEQUATE SAMPLE SIZE AND TRIAL DURATION AND APPROPRIATE ENDPOINTS ARE REQUIRED FOR PRECLINICAL ASSESSMENT OF EXPERIMENTAL PAH THERAPIES.	2013	
                                                                                                                                                                                                                                           
3  2356  33 EPIGENETIC REGULATION OF PULMONARY ARTERIAL HYPERTENSION-INDUCED VASCULAR AND RIGHT VENTRICULAR REMODELING: NEW OPPORTUNITIES? PULMONARY ARTERY HYPERTENSION (PAH) IS A RARE CHRONIC DISEASE WITH HIGH IMPACT ON PATIENTS' QUALITY OF LIFE AND CURRENTLY NO AVAILABLE CURE. PAH IS CHARACTERIZED BY CONSTANT REMODELING OF THE PULMONARY ARTERY BY INCREASED PROLIFERATION AND MIGRATION OF PULMONARY ARTERIAL SMOOTH MUSCLE CELLS (PASMCS), FIBROBLASTS (FBS) AND ENDOTHELIAL CELLS (ECS). THIS REMODELING EVENTUALLY LEADS TO INCREASED PRESSURE IN THE RIGHT VENTRICLE (RV) AND SUBSEQUENT RIGHT VENTRICLE HYPERTROPHY (RVH) WHICH, WHEN LEFT UNTREATED, PROGRESSES INTO RIGHT VENTRICLE FAILURE (RVF). PAH CAN NOT ONLY ORIGINATE FROM HERITABLE MUTATIONS, BUT ALSO DEVELOP AS A CONSEQUENCE OF CONGENITAL HEART DISEASE, EXPOSURE TO DRUGS OR TOXINS, HIV, CONNECTIVE TISSUE DISEASE OR BE IDIOPATHIC. WHILE MUCH ATTENTION WAS DRAWN INTO INVESTIGATING AND DEVELOPING THERAPIES RELATED TO THE MOST WELL UNDERSTOOD SIGNALING PATHWAYS IN PAH, IN THE LAST DECADE, A SHIFT TOWARDS UNDERSTANDING THE EPIGENETIC MECHANISMS DRIVING THE DISEASE OCCURRED. IN THIS REVIEW, WE REFLECT ON THE DIFFERENT EPIGENETIC REGULATORY FACTORS THAT ARE ASSOCIATED WITH THE PATHOLOGY OF RV REMODELING, AND ON THEIR RELEVANCE TOWARDS A BETTER UNDERSTANDING OF THE DISEASE AND SUBSEQUENTLY, THE DEVELOPMENT OF NEW AND MORE EFFICIENT THERAPEUTIC STRATEGIES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4  3719  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5  2537  20 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   543  38 ATRIAL FIBRILLATION IS ASSOCIATED WITH HYPERMETHYLATION IN HUMAN LEFT ATRIUM, AND TREATMENT WITH DECITABINE REDUCES ATRIAL TACHYARRHYTHMIAS IN SPONTANEOUSLY HYPERTENSIVE RATS. ATRIAL FIBRILLATION (AF) IS THE MOST COMMON CARDIAC ARRHYTHMIA. AS THE MOLECULAR MECHANISMS UNDERLYING THE PATHOLOGY ARE LARGELY UNKNOWN, THIS CARDIAC ARRHYTHMIA REMAINS DIFFICULT TO TREAT. TO IDENTIFY SPECIFIC MOLECULAR ACTORS INVOLVED IN AF, WE HAVE PERFORMED A TRANSCRIPTOMIC ANALYSIS ON LEFT ATRIUM (LA) FROM PATIENTS WITH VALVULAR HEART DISEASE WITH OR WITHOUT AF. WE SHOWED THAT 1627 GENES HAD ALTERED BASAL EXPRESSION LEVEL IN LA TISSUE OF AF PATIENTS COMPARED WITH THE CONTROL GROUP. THE SIGNIFICANTLY ENRICHED GENE ONTOLOGY BIOLOGICAL PROCESS "ANATOMICAL STRUCTURE MORPHOGENESIS" CONTAINED THE HIGHEST NUMBER OF GENES IN LINE WITH CHANGES IN STRUCTURE THAT OCCUR WHEN THE HUMAN HEART REMODELS FOLLOWING AF DEVELOPMENT (IE, LA DILATATION AND INTERSTITIAL FIBROSIS). WE THEN FOCUSED THE STUDY ON PITX2 (PAIRED-LIKE HOMEODOMAIN 2), BEING THE MOST ALTERED TRANSCRIPTION FACTOR IN LA FROM AF PATIENTS AND FROM WHICH COMPELLING EVIDENCE HAVE INDICATED THAT ITS REDUCED EXPRESSION CAN BE CONSIDERED AS A MARKER FOR THE DISEASE. IN ADDITION, ITS EXPRESSION WAS INVERSELY CORRELATED WITH LA SIZE. WE DEMONSTRATED THAT AF IS ASSOCIATED WITH PITX2 PROMOTER HYPERMETHYLATION BOTH IN HUMANS AND ARRHYTHMIC AGING SPONTANEOUSLY HYPERTENSIVE RATS. CHRONIC ADMINISTRATION OF A DNA METHYLATION INHIBITOR (IE, 5-AZA-2'-DEOXYCITIDINE) IMPROVED ECG ARRHYTHMIC PROFILES AND SUPEROXIDE DISMUTASE ACTIVITIES AND REDUCED FIBROSIS IN THE LEFT VENTRICLE OF SPONTANEOUSLY HYPERTENSIVE RATS. TAKEN TOGETHER, THESE DATA SUPPORT THE NOTION THAT AF IS ASSOCIATED WITH EPIGENETIC CHANGES IN LA AND PROVIDE A PROOF-OF-CONCEPT THAT HYPOMETHYLATING AGENTS HAVE TO BE CONSIDERED IN THE TREATMENT OF ATRIAL ARRHYTHMIAS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7   245  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9  5572  25 ROLE OF MICRORNA IN DIABETIC CARDIOMYOPATHY: FROM MECHANISM TO INTERVENTION. DIABETIC CARDIOMYOPATHY IS A CHRONIC AND IRREVERSIBLE HEART COMPLICATION IN DIABETIC PATIENTS, AND IS CHARACTERIZED BY COMPLEX PATHOPHYSIOLOGIC EVENTS INCLUDING EARLY DIASTOLIC DYSFUNCTION, CARDIAC HYPERTROPHY, VENTRICULAR DILATION AND SYSTOLIC DYSFUNCTION, EVENTUALLY RESULTING IN HEART FAILURE. DESPITE THESE CHARACTERISTICS, THE UNDERLYING MECHANISMS LEADING TO DIABETIC CARDIOMYOPATHY ARE STILL ELUSIVE. RECENT STUDIES HAVE IMPLICATED MICRORNA, A SMALL AND HIGHLY CONSERVED NON-CODING RNA MOLECULE, IN THE ETIOLOGY OF DIABETES AND ITS COMPLICATIONS, SUGGESTING A POTENTIALLY NOVEL APPROACH FOR THE DIAGNOSIS AND TREATMENT OF DIABETIC CARDIOMYOPATHY. THIS BRIEF REVIEW AIMS AT CAPTURING RECENT STUDIES RELATED TO THE ROLE OF MICRORNA IN DIABETIC CARDIOMYOPATHY. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: GENETIC AND EPIGENETIC CONTROL OF HEART FAILURE - EDITED BY JUN REN & MEGAN YINGMEI ZHANG.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10   246  40 ADULT STEM CELL THERAPY FOR CARDIAC REPAIR IN PATIENTS AFTER ACUTE MYOCARDIAL INFARCTION LEADING TO ISCHEMIC HEART FAILURE: AN OVERVIEW OF EVIDENCE FROM THE RECENT CLINICAL TRIALS. BACKGROUND: CARDIOVASCULAR DISEASES (CVD) STILL REPRESENT THE LEADING CAUSE OF MORTALITY WORLDWIDE, DESPITE THE REMARKABLE ADVANCES IN INTERVENTIONAL CARDIOLOGY, CARDIAC SURGERY, AND MODERN PHARMACOTHERAPY, PARTICULARLY IN THE SETTING OF ACUTE MYOCARDIAL INFARCTION (AMI), CHRONIC ISCHEMIC HEART FAILURE (HF), CARDIOMYOPATHY (CM), AND THE ASSOCIATED LEFT VENTRICULAR (LV) DYSFUNCTION. A SIGNIFICANT LOSS OF CARDIOMYOCYTES THAT UNDERLIES ALL OF THESE CONDITIONS WAS PREVIOUSLY CONSIDERED IRREVERSIBLE. HOWEVER, CURRENT EVIDENCE INDICATES THAT THE HUMAN HEART HAS SOME POTENTIAL FOR REPAIR, AND OVER THE PAST DECADE, MANY RESEARCH STUDIES HAVE BEEN EXPLORING THE USE OF STEM CELLS (SCS) TO FACILITATE RESTORATION OF MYOCARDIUM. CONSEQUENTLY, THE SAFETY, FEASIBILITY, AND EFFECTIVENESS OF SC THERAPY HAVE BEEN REPORTED IN MANY RANDOMIZED CLINICAL TRIALS (RCTS), USING DIFFERENT LINEAGES OF ADULT SCS. NEVERTHELESS, THE CLINICAL BENEFITS OF SC THERAPY ARE NOT YET WELL ESTABLISHED. IN THE NEAR FUTURE, UNDERSTANDING OF THE COMPLEX INTERRELATIONS BETWEEN SCS, PARACRINE FACTORS, GENETIC OR EPIGENETIC PREDISPOSITIONS, AND MYOCARDIAL MICROENVIRONMENT, IN THE CONTEXT OF AN INDIVIDUAL PATIENT, WILL BE CRUCIAL FOR TRANSLATION OF THIS KNOWLEDGE INTO PRACTICAL DEVELOPMENT OF SUCCESSFUL, LONG-TERM REGENERATIVE SC THERAPEUTIC APPLICATIONS, IN A GROWING POPULATION OF PATIENTS SUFFERING FROM PREVIOUS MYOCARDIAL INFARCTION (MI) LEADING TO CHRONIC ISCHEMIC CARDIOMYOPATHY. CONCLUSION: THIS OVERVIEW HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF ADULT SCS IN TERMS OF THEIR POSSIBLE REGENERATIVE CAPACITY, SAFETY, AND CLINICAL OUTCOMES, IN PATIENTS WITH AMI, AND/OR SUBSEQUENT HF (DUE TO CHRONIC ISCHEMIC CARDIOMYOPATHY). THIS REVIEW WAS BASED UPON PUBMED DATABASE SEARCH FOR TRIALS ON SC THERAPY, IN PATIENTS WITH AMI AND HF, AND THE MAIN TIMEFRAME WAS SET FROM 2006 TO 2016.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11   201  51 ACTIVATING TRANSCRIPTION FACTOR 3 PROTECTS AGAINST PRESSURE-OVERLOAD HEART FAILURE VIA THE AUTOPHAGY MOLECULE BECLIN-1 PATHWAY. ACTIVATING TRANSCRIPTION FACTOR 3 (ATF3), A CAMP RESPONSE ELEMENT-BINDING PROTEIN/ATF FAMILY TRANSCRIPTION FACTORS MEMBER, HAS BEEN IMPLICATED IN THE CARDIOVASCULAR AND INFLAMMATORY SYSTEM AND IS RAPIDLY INDUCED BY ISCHEMIC-REPERFUSION INJURIES. WE PERFORMED TRANSVERSE AORTIC BANDING (TAB) EXPERIMENTS USING ATF3 GENE-DELETED MICE (ATF3(-/-)) AND WILD-TYPE (WT) MICE TO DETERMINE WHAT EFFECT IT MIGHT HAVE ON HEART FAILURE INDUCED BY PRESSURE OVERLOADING. COMPARED WITH THE WT MICE, ATF3(-/-) MICE WERE FOUND BY ECHOCARDIOGRAPHY TO HAVE DECREASED LEFT VENTRICULAR CONTRACTILITY WITH LOSS OF NORMAL CARDIAC HYPERTROPHIC REMODELING. THE ATF3(-/-) MICE HAD GREATER NUMBERS OF TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE-MEDIATED DIGOXIGENIN-DEOXYURIDINE NICK-END LABELING-POSITIVE CELLS AND HIGHER LEVELS OF ACTIVATED CASPASE-3, AS WELL AS MORE APOPTOSIS. RESTORATION OF ATF3 EXPRESSION IN THE HEART OF ATF3(-/-) MICE BY ADENOVIRUS-INDUCED ATF3 TREATMENT SIGNIFICANTLY IMPROVED CARDIAC CONTRACTILITY AFTER TAB. THE RESULTS FROM MOLECULAR AND BIOCHEMICAL ANALYSES, INCLUDING CHROMATIN IMMUNE-PRECIPITATION AND IN VITRO /IN VIVO PROMOTER ASSAYS, SHOWED THAT ATF3 BOUND TO THE ATF/CAMP RESPONSE ELEMENT OF THE BECLIN-1 PROMOTER AND THAT ATF3 REDUCED AUTOPHAGY VIA SUPPRESSION OF THE BECLIN-1-DEPENDENT PATHWAY. FURTHERMORE, INFUSION OF TERT-BUTYLHYDROQUINONE (TBHQ), A SELECTIVE ATF3 INDUCER, INCREASED THE EXPRESSION OF ATF3 VIA THE NUCLEAR FACTOR ERYTHROID 2-RELATED TRANSCRIPTIONAL FACTOR, INHIBITED TAB-INDUCED CARDIAC DILATATION, AND INCREASED LEFT VENTRICULAR CONTRACTILITY, THEREBY RESCUING HEART FAILURE. OUR STUDY IDENTIFIED A NEW EPIGENETIC REGULATION MEDIATED BY THE STRESS-INDUCIBLE GENE ATF3 ON TAB-INDUCED CARDIAC DYSFUNCTION. THESE FINDINGS SUGGEST THAT THE ATF3 ACTIVATOR TBHQ MAY HAVE THERAPEUTIC POTENTIAL FOR THE TREATMENT OF PRESSURE-OVERLOAD HEART FAILURE INDUCED BY CHRONIC HYPERTENSION OR OTHER PRESSURE OVERLOAD MECHANISMS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
12  5048  40 PHARMACOLOGICAL APPROACHES IN EITHER INTERMITTENT OR PERMANENT HYPOXIA: A TALE OF TWO EXPOSURES. HYPOXIA INDUCES SEVERAL RESPONSES AT CARDIOVASCULAR, PULMONARY AND REPRODUCTIVE LEVELS, WHICH MAY LEAD TO CHRONIC DISEASES. THIS IS RELEVANT IN HUMAN POPULATIONS EXPOSED TO HIGH ALTITUDE (HA), IN EITHER CHRONIC CONTINUOUS (PERMANENT INHABITANTS) OR INTERMITTENT FASHION (HA WORKERS, TOURISTS AND MOUNTAINEERS). IN CHILE, IT IS ESTIMATED THAT 1.000.000 PEOPLE LIVE AT HIGHLANDS AND MORE THAN 55.000 WORK IN HA SHIFTS. INITIAL RESPONSES TO HYPOXIA ARE COMPENSATORY AND INDUCE ACTIVATION OF CARDIOPROTECTIVE MECHANISMS, SUCH AS THOSE SEEN UNDER INTERMITTENT HYPOBARIC (IH) HYPOXIA, EVENTS THAT COULD MEDIATE PRECONDITIONING. HOWEVER, WHENEVER HYPOXIA IS PROLONGED, THE CHRONIC ACTIVATION OF CELLULAR RESPONSES INDUCES LONG-LASTING MODIFICATIONS THAT MAY RESULT IN ACCLIMATIZATION OR PRODUCE MALADAPTIVE CHANGES WITH INCREASE IN CARDIOVASCULAR RISK. HA EXPOSURE DURING PREGNANCY INDUCES HYPOXIA AND OXIDATIVE STRESS, WHICH IN TURN MAY PROMOTE CELLULAR RESPONSES AND EPIGENETIC MODIFICATIONS RESULTING IN SEVERE IMPAIRMENT IN GROWTH AND DEVELOPMENT. SADLY, THIS CONDITION IS ACCOMPANIED WITH AN INCREASED FETAL AND NEONATAL MORBI-MORTALITY. FURTHER, DEVELOPMENTAL HYPOXIA MAY PROGRAM CARDIO-PULMONARY CIRCULATIONS LATER IN POSTNATAL LIFE, ENDING IN VASCULAR STRUCTURAL AND FUNCTIONAL ALTERATIONS WITH AUGMENTED RISK ON PULMONARY AND CARDIOVASCULAR FAILURE. ADDITIONALLY, PERMANENT HA INHABITANTS HAVE AUGMENTED RISK AND PREVALENCE OF CHRONIC HYPOXIC PULMONARY HYPERTENSION, RIGHT VENTRICULAR HYPERTROPHY AND CARDIOPULMONARY REMODELING. SIMILAR RESPONSES ARE SEEN IN ADULTS THAT ARE INTERMITTENTLY EXPOSED TO CHRONIC HYPOXIA (CH) SUCH AS SHIFT WORKERS IN HA AREAS. THE MECHANISMS INVOLVED DETERMINING THE IMMEDIATE, SHORT AND LONG-LASTING EFFECTS ARE STILL UNCLEAR. FOR SEVERAL YEARS, THE STUDY OF THE RESPONSES TO HYPOXIC INSULTS AND PHARMACOLOGICAL TARGETS HAS BEEN THE MOTIVATION OF OUR GROUP. THIS REVIEW DESCRIBES SOME OF THE MECHANISMS UNDERLYING HYPOXIC RESPONSES AND POTENTIAL THERAPEUTIC APPROACHES WITH ANTIOXIDANTS SUCH AS MELATONIN, ASCORBATE, OMEGA 3 (OMEGA3) OR COMPOUNDS THAT INCREASE THE NITRIC OXIDE (NO) BIOAVAILABILITY.	2015	
                                                                                                                                                                                                                                                                                                                                         
13   465  37 ARE TARGETED THERAPIES FOR DIABETIC CARDIOMYOPATHY ON THE HORIZON? DIABETES INCREASES THE RISK OF HEART FAILURE APPROXIMATELY 2.5-FOLD, INDEPENDENT OF CORONARY ARTERY DISEASE AND OTHER COMORBIDITIES. THIS PROCESS, TERMED DIABETIC CARDIOMYOPATHY, IS CHARACTERIZED BY INITIAL IMPAIRMENT OF LEFT VENTRICULAR (LV) RELAXATION FOLLOWED BY LV CONTRACTILE DYSFUNCTION. POST-MORTEM EXAMINATION REVEALS THAT HUMAN DIASTOLIC DYSFUNCTION IS CLOSELY ASSOCIATED WITH LV DAMAGE, INCLUDING CARDIOMYOCYTE HYPERTROPHY, APOPTOSIS AND FIBROSIS, WITH IMPAIRED CORONARY MICROVASCULAR PERFUSION. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERPINNING THE CHARACTERISTIC FEATURES OF DIABETIC CARDIOMYOPATHY REMAIN POORLY UNDERSTOOD, ALTHOUGH MULTIPLE FACTORS INCLUDING ALTERED LIPID METABOLISM, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM (ER) STRESS, INFLAMMATION, AS WELL AS EPIGENETIC CHANGES, ARE IMPLICATED. DESPITE A RECENT RISE IN RESEARCH INTERROGATING THESE MECHANISMS AND AN INCREASED UNDERSTANDING OF THE CLINICAL IMPORTANCE OF DIABETIC CARDIOMYOPATHY, THERE REMAINS A LACK OF SPECIFIC TREATMENT STRATEGIES. HOW THE CHRONIC METABOLIC DISTURBANCES OBSERVED IN DIABETES LEAD TO STRUCTURAL AND FUNCTIONAL CHANGES REMAINS A PERTINENT QUESTION, AND IT IS HOPED THAT RECENT ADVANCES, PARTICULARLY IN THE AREA OF EPIGENETICS, AMONG OTHERS, MAY PROVIDE SOME ANSWERS. THIS REVIEW HENCE EXPLORES THE TEMPORAL ONSET OF THE PATHOLOGICAL FEATURES OF DIABETIC CARDIOMYOPATHY, AND THEIR RELATIVE CONTRIBUTION TO THE RESULTANT DISEASE PHENOTYPE, AS WELL AS BOTH CURRENT AND POTENTIAL THERAPEUTIC OPTIONS. THE EMERGENCE OF GLUCOSE-OPTIMIZING AGENTS, NAMELY GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS AND SODIUM/GLUCOSE CO-TRANSPORTER (SGLT)2 INHIBITORS THAT CONFER BENEFITS ON CARDIOVASCULAR OUTCOMES, TOGETHER WITH NOVEL EXPERIMENTAL APPROACHES, HIGHLIGHT A NEW AND EXCITING ERA IN DIABETES RESEARCH, WHICH IS LIKELY TO RESULT IN MAJOR CLINICAL IMPACT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  4415  33 MOLECULAR AND CELLULAR MECHANISMS THAT INDUCE ARTERIAL CALCIFICATION BY INDOXYL SULFATE AND P-CRESYL SULFATE. THE PROTEIN-BOUND UREMIC TOXINS, INDOXYL SULFATE (IS) AND P-CRESYL SULFATE (PCS), ARE CONSIDERED TO BE HARMFUL VASCULAR TOXINS. ARTERIAL MEDIA CALCIFICATION, OR THE DEPOSITION OF CALCIUM PHOSPHATE CRYSTALS IN THE ARTERIES, CONTRIBUTES SIGNIFICANTLY TO CARDIOVASCULAR COMPLICATIONS, INCLUDING LEFT VENTRICULAR HYPERTROPHY, HYPERTENSION, AND IMPAIRED CORONARY PERFUSION IN THE ELDERLY AND PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) AND DIABETES. RECENTLY, WE REPORTED THAT BOTH IS AND PCS TRIGGER MODERATE TO SEVERE CALCIFICATION IN THE AORTA AND PERIPHERAL VESSELS OF CKD RATS. THIS REVIEW DESCRIBES THE MOLECULAR AND CELLULAR MECHANISMS BY WHICH THESE UREMIC TOXINS INDUCE ARTERIAL MEDIA CALCIFICATION. A COMPLEX INTERPLAY BETWEEN INFLAMMATION, COAGULATION, AND LIPID METABOLISM PATHWAYS, INFLUENCED BY EPIGENETIC FACTORS, IS CRUCIAL IN IS/PCS-INDUCED ARTERIAL MEDIA CALCIFICATION. HIGH LEVELS OF GLUCOSE ARE LINKED TO THESE EVENTS, SUGGESTING THAT A GOOD BALANCE BETWEEN GLUCOSE AND LIPID LEVELS MIGHT BE IMPORTANT. ON THE CELLULAR LEVEL, EFFECTS ON ENDOTHELIAL CELLS, WHICH ACT AS THE PRIMARY SENSORS OF CIRCULATING PATHOLOGICAL TRIGGERS, MIGHT BE AS IMPORTANT AS THOSE ON VASCULAR SMOOTH MUSCLE CELLS. ENDOTHELIAL DYSFUNCTION, PROVOKED BY IS AND PCS TRIGGERED OXIDATIVE STRESS, MAY BE CONSIDERED A KEY EVENT IN THE ONSET AND DEVELOPMENT OF ARTERIAL MEDIA CALCIFICATION. IN THIS REVIEW A NUMBER OF IMPORTANT OUTSTANDING QUESTIONS SUCH AS THE ROLE OF MIRNA'S, PHENOTYPIC SWITCHING OF BOTH ENDOTHELIAL AND VASCULAR SMOOTH MUSCLE CELLS AND NEW TYPES OF PROGRAMMED CELL DEATH IN ARTERIAL MEDIA CALCIFICATION RELATED TO PROTEIN-BOUND UREMIC TOXINS ARE PUT FORWARD AND DISCUSSED.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15   750  26 CARDIAC INVOLVEMENT IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES. AUTHORS HAVE REVIEWED LITERATURE ABOUT THE MANAGEMENT OF PATIENTS WITH CARDIOLOGIC DISEASE OCCURRING SECONDARY TO HEMATOLOGIC PATHOLOGY ITSELF OR ITS THERAPY, WITH A FOCUS ON INFILTRATION OF MYOCARDIUM IN ACUTE AND CHRONIC LEUKEMIA, LYMPHOMA, MULTIPLE MYELOMA, AND HYPEREOSINOPHILIC SYNDROME. MOREOVER, THEY EVALUATED CHEMOTHERAPY-ASSOCIATED TOXICITY, PARTICULARLY FOR NEW DRUGS SUCH AS MONOCLONAL ANTIBODY THERAPY, TYROSINE KINASE INHIBITORS, ARSENIC TRIOXIDE, BORTEZOMIB, AND EPIGENETIC THERAPY. IN FACT, CARDIAC TOXICITY MAY RANGE FROM ASYMPTOMATIC SUBCLINICAL ABNORMALITIES, SUCH AS ELECTROCARDIOGRAPHIC CHANGES AND LEFT VENTRICULAR EJECTION DECLINE, TO LIFE-THREATENING EVENTS AND LEAD TO CHEMOTHERAPY DOSE REDUCTION AND DELAY AND, IN SOME CASES, FOR PATIENTS WITH SEVERE SIDE EFFECTS, DISCONTINUATION OF TREATMENT. FINALLY, THEY DISCUSSED ON THE IDENTIFICATION OF EARLY MARKERS OF CARDIAC INJURY AND ON CARDIAC STEM CELL THERAPY AS A PROMISING APPROACH TO FACILITATE MYOCARDIAL REGENERATION.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16  2278  37 EPIGENETIC REGULATION BY SUV4-20H1 IN CARDIOPULMONARY PROGENITOR CELLS IS REQUIRED TO PREVENT PULMONARY HYPERTENSION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: THE PATHOGENESIS OF LIFE-THREATENING CARDIOPULMONARY DISEASES SUCH AS PULMONARY HYPERTENSION (PH) AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ORIGINATES FROM A COMPLEX INTERPLAY OF ENVIRONMENTAL FACTORS AND GENETIC PREDISPOSITIONS THAT IS NOT FULLY UNDERSTOOD. LIKEWISE, LITTLE IS KNOWN ABOUT DEVELOPMENTAL ABNORMALITIES OR EPIGENETIC DYSREGULATIONS THAT MIGHT PREDISPOSE FOR PH OR COPD IN ADULT INDIVIDUALS. METHODS: TO IDENTIFY PATHOLOGY-ASSOCIATED EPIGENETIC ALTERATION IN DISEASED LUNG TISSUES, WE SCREENED A COHORT OF HUMAN PATIENTS WITH PH AND COPD FOR CHANGES OF HISTONE MODIFICATIONS BY IMMUNOFLUORESCENCE STAINING. TO ANALYZE THE FUNCTION OF H4K20ME2/3 IN LUNG PATHOGENESIS, WE DEVELOPED A SERIES OF SUV4-20H1 KNOCKOUT MOUSE LINES TARGETING CARDIOPULMONARY PROGENITOR CELLS AND DIFFERENT HEART AND LUNG CELL TYPES, FOLLOWED BY HEMODYNAMIC STUDIES AND MORPHOMETRIC ASSESSMENT OF TISSUE SAMPLES. MOLECULAR, CELLULAR, AND BIOCHEMICAL TECHNIQUES WERE APPLIED TO ANALYZE THE FUNCTION OF SUV4-20H1-DEPENDENT EPIGENETIC PROCESSES IN CARDIOPULMONARY PROGENITOR CELLS AND THEIR DERIVATIVES. RESULTS: WE DISCOVERED A STRONG REDUCTION OF THE HISTONE MODIFICATIONS OF H4K20ME2/3 IN HUMAN PATIENTS WITH COPD BUT NOT PATIENTS WITH PH THAT DEPEND ON THE ACTIVITY OF THE H4K20 DI-METHYLTRANSFERASE SUV4-20H1. LOSS OF SUV4-20H1 IN CARDIOPULMONARY PROGENITOR CELLS CAUSED A COPD-LIKE/PH PHENOTYPE IN MICE INCLUDING THE FORMATION OF PERIVASCULAR TERTIARY LYMPHOID TISSUE AND GOBLET CELL HYPERPLASIA, HYPERPROLIFERATION OF SMOOTH MUSCLE CELLS/MYOFIBROBLASTS, IMPAIRED ALVEOLARIZATION AND MATURATION DEFECTS OF THE MICROVASCULATURE LEADING TO MASSIVE RIGHT VENTRICULAR DILATATION AND PREMATURE DEATH. MECHANISTICALLY, SUV4-20H1 BINDS DIRECTLY TO THE 5'-UPSTREAM REGULATORY ELEMENT OF THE SUPEROXIDE DISMUTASE 3 (SOD3) GENE TO REPRESS ITS EXPRESSION. INCREASED LEVELS OF THE EXTRACELLULAR SOD3 ENZYME IN SUV4-20H1 MUTANTS INCREASES HYDROGEN PEROXIDE CONCENTRATIONS, CAUSING VASCULAR DEFECTS AND IMPAIRING ALVEOLARIZATION. CONCLUSIONS: OUR FINDINGS REVEAL A PIVOTAL ROLE OF THE HISTONE MODIFIER SUV4-20H1 IN CARDIOPULMONARY CODEVELOPMENT AND UNCOVER THE DEVELOPMENTAL ORIGINS OF CARDIOPULMONARY DISEASES. WE ASSUME THAT THE STUDY WILL FACILITATE THE UNDERSTANDING OF PATHOGENIC EVENTS CAUSING PH AND COPD AND AID THE DEVELOPMENT OF EPIGENETIC DRUGS FOR THE TREATMENT OF CARDIOPULMONARY DISEASES.	2021	

17  4978  28 PATHOPHYSIOLOGY AND NEW ADVANCES IN PULMONARY HYPERTENSION. PULMONARY HYPERTENSION IS A PROGRESSIVE AND OFTEN FATAL CARDIOPULMONARY CONDITION CHARACTERISED BY INCREASED PULMONARY ARTERIAL PRESSURE, STRUCTURAL CHANGES IN THE PULMONARY CIRCULATION, AND THE FORMATION OF VASO-OCCLUSIVE LESIONS. THESE CHANGES LEAD TO INCREASED RIGHT VENTRICULAR AFTERLOAD, WHICH OFTEN PROGRESSES TO MALADAPTIVE RIGHT VENTRICULAR REMODELLING AND EVENTUALLY DEATH. PULMONARY ARTERIAL HYPERTENSION REPRESENTS ONE OF THE MOST SEVERE AND BEST STUDIED TYPES OF PULMONARY HYPERTENSION AND IS CONSISTENTLY TARGETED BY DRUG TREATMENTS. THE UNDERLYING MOLECULAR PATHOGENESIS OF PULMONARY HYPERTENSION IS A COMPLEX AND MULTIFACTORIAL PROCESS, BUT CAN BE CHARACTERISED BY SEVERAL HALLMARKS: INFLAMMATION, IMPAIRED ANGIOGENESIS, METABOLIC ALTERATIONS, GENETIC OR EPIGENETIC ABNORMALITIES, INFLUENCE OF SEX AND SEX HORMONES, AND ABNORMALITIES IN THE RIGHT VENTRICLE. CURRENT TREATMENTS FOR PULMONARY ARTERIAL HYPERTENSION AND SOME OTHER TYPES OF PULMONARY HYPERTENSION TARGET PATHWAYS INVOLVED IN THE CONTROL OF PULMONARY VASCULAR TONE AND PROLIFERATION; HOWEVER, THESE TREATMENTS HAVE LIMITED EFFICACY ON PATIENT OUTCOMES. THIS REVIEW DESCRIBES KEY FEATURES OF PULMONARY HYPERTENSION, DISCUSSES CURRENT AND EMERGING THERAPEUTIC INTERVENTIONS, AND POINTS TO FUTURE DIRECTIONS FOR RESEARCH AND PATIENT CARE. BECAUSE MOST PROGRESS IN THE SPECIALTY HAS BEEN MADE IN PULMONARY ARTERIAL HYPERTENSION, THIS REVIEW FOCUSES ON THIS TYPE OF PULMONARY HYPERTENSION. THE REVIEW HIGHLIGHTS KEY PATHOPHYSIOLOGICAL CONCEPTS AND EMERGING THERAPEUTIC DIRECTIONS, TARGETING INFLAMMATION, CELLULAR METABOLISM, GENETICS AND EPIGENETICS, SEX HORMONE SIGNALLING, BONE MORPHOGENETIC PROTEIN SIGNALLING, AND INHIBITION OF TYROSINE KINASE RECEPTORS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  5075  26 PHYSIOLOGICAL ADAPTATION OF THE GROWTH-RESTRICTED FETUS. THE GROWTH-RESTRICTED FETUS IN UTERO IS EXPOSED TO A HOSTILE ENVIRONMENT AND SUFFERS UNDERNUTRITION AND HYPOXIA. TO COPE WITH THE STRESS, THE FETUS CHANGES ITS PHYSIOLOGICAL FUNCTIONS. THESE ADAPTIVE CHANGES AID INTRAUTERINE SURVIVAL; HOWEVER, THEY CAN LEAD TO PERMANENT FUNCTIONAL AND STRUCTURAL CHANGES THAT CAN CONTRIBUTE TO THE DEVELOPMENT OF SERIOUS CHRONIC DISEASES LATER IN LIFE. EPIGENETIC MECHANISMS ARE AN IMPORTANT PART OF THE PATHOPHYSIOLOGICAL PROCESSES BEHIND THIS "DEVELOPMENTAL ORIGIN OF ADULT DISEASES." THE DOMINANT CARDIOVASCULAR ADAPTIVE CHANGE IS THE REDISTRIBUTION OF BLOOD FLOW IN HYPOXIC FETUSES, WITH PREFERENTIAL SUPPLY OF BLOOD TO THE FETAL BRAIN, MYOCARDIUM, AND ADRENAL GLANDS. THE PROPORTION OF BLOOD FROM THE UMBILICAL VEIN TO THE DUCTUS VENOSUS AND FORAMEN OVALE INCREASES, WHICH INCREASES THE CARDIAC OUTPUT OF THE LEFT HEART VENTRICLE. THE INCREASED PERFUSION OF FETAL BRAIN CAN BE FOLLOWED WITH DOPPLER ULTRASOUND AS INCREASED DIASTOLIC VELOCITIES AND DECREASED PULSATILITY INDEX IN THE MIDDLE CEREBRAL ARTERY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19  1157  38 CONTAMINANT METALS AS CARDIOVASCULAR RISK FACTORS: A SCIENTIFIC STATEMENT FROM THE AMERICAN HEART ASSOCIATION. EXPOSURE TO ENVIRONMENTAL POLLUTANTS IS LINKED TO INCREASED RISK OF CARDIOVASCULAR DISEASE. BEYOND THE EXTENSIVE EVIDENCE FOR PARTICULATE AIR POLLUTION, ACCUMULATING EVIDENCE SUPPORTS THAT EXPOSURE TO NONESSENTIAL METALS SUCH AS LEAD, CADMIUM, AND ARSENIC IS A SIGNIFICANT CONTRIBUTOR TO CARDIOVASCULAR DISEASE WORLDWIDE. HUMANS ARE EXPOSED TO METALS THROUGH AIR, WATER, SOIL, AND FOOD AND EXTENSIVE INDUSTRIAL AND PUBLIC USE. CONTAMINANT METALS INTERFERE WITH CRITICAL INTRACELLULAR REACTIONS AND FUNCTIONS LEADING TO OXIDATIVE STRESS AND CHRONIC INFLAMMATION THAT RESULT IN ENDOTHELIAL DYSFUNCTION, HYPERTENSION, EPIGENETIC DYSREGULATION, DYSLIPIDEMIA, AND CHANGES IN MYOCARDIAL EXCITATION AND CONTRACTILE FUNCTION. LEAD, CADMIUM, AND ARSENIC HAVE BEEN LINKED TO SUBCLINICAL ATHEROSCLEROSIS, CORONARY ARTERY STENOSIS, AND CALCIFICATION AS WELL AS TO INCREASED RISK OF ISCHEMIC HEART DISEASE AND STROKE, LEFT VENTRICULAR HYPERTROPHY AND HEART FAILURE, AND PERIPHERAL ARTERY DISEASE. EPIDEMIOLOGICAL STUDIES SHOW THAT EXPOSURE TO LEAD, CADMIUM, OR ARSENIC IS ASSOCIATED WITH CARDIOVASCULAR DEATH MOSTLY ATTRIBUTABLE TO ISCHEMIC HEART DISEASE. PUBLIC HEALTH MEASURES REDUCING METAL EXPOSURE ARE ASSOCIATED WITH REDUCTIONS IN CARDIOVASCULAR DISEASE DEATH. POPULATIONS OF COLOR AND LOW SOCIOECONOMIC MEANS ARE MORE COMMONLY EXPOSED TO METALS AND THEREFORE AT GREATER RISK OF METAL-INDUCED CARDIOVASCULAR DISEASE. TOGETHER WITH STRENGTHENING PUBLIC HEALTH MEASURES TO PREVENT METAL EXPOSURES, DEVELOPMENT OF MORE SENSITIVE AND SELECTIVE MEASUREMENT MODALITIES, CLINICAL MONITORING OF METAL EXPOSURES, AND THE DEVELOPMENT OF METAL CHELATION THERAPIES COULD FURTHER DIMINISH THE BURDEN OF CARDIOVASCULAR DISEASE ATTRIBUTABLE TO METAL EXPOSURE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  4191  34 METABOLIC LANDSCAPE IN CARDIAC AGING: INSIGHTS INTO MOLECULAR BIOLOGY AND THERAPEUTIC IMPLICATIONS. CARDIAC AGING IS EVIDENT BY A REDUCTION IN FUNCTION WHICH SUBSEQUENTLY CONTRIBUTES TO HEART FAILURE. THE METABOLIC MICROENVIRONMENT HAS BEEN IDENTIFIED AS A HALLMARK OF MALIGNANCY, BUT RECENT STUDIES HAVE SHED LIGHT ON ITS ROLE IN CARDIOVASCULAR DISEASES (CVDS). VARIOUS METABOLIC PATHWAYS IN CARDIOMYOCYTES AND NONCARDIOMYOCYTES DETERMINE CELLULAR SENESCENCE IN THE AGING HEART. METABOLIC ALTERATION IS A COMMON PROCESS THROUGHOUT CARDIAC DEGENERATION. IMPORTANTLY, THE INVOLVEMENT OF CELLULAR SENESCENCE IN CARDIAC INJURIES, INCLUDING HEART FAILURE AND MYOCARDIAL ISCHEMIA AND INFARCTION, HAS BEEN REPORTED. HOWEVER, METABOLIC COMPLEXITY AMONG HUMAN AGING HEARTS HINDERS THE DEVELOPMENT OF STRATEGIES THAT TARGETS METABOLIC SUSCEPTIBILITY. ADVANCES OVER THE PAST DECADE HAVE LINKED CELLULAR SENESCENCE AND FUNCTION WITH THEIR METABOLIC REPROGRAMMING PATHWAY IN CARDIAC AGING, INCLUDING AUTOPHAGY, OXIDATIVE STRESS, EPIGENETIC MODIFICATIONS, CHRONIC INFLAMMATION, AND MYOCYTE SYSTOLIC PHENOTYPE REGULATION. IN ADDITION, METABOLIC STATUS IS INVOLVED IN CRUCIAL ASPECTS OF MYOCARDIAL BIOLOGY, FROM FIBROSIS TO HYPERTROPHY AND CHRONIC INFLAMMATION. HOWEVER, FURTHER ELUCIDATION OF THE METABOLISM INVOLVEMENT IN CARDIAC DEGENERATION IS STILL NEEDED. THUS, DECIPHERING THE MECHANISMS UNDERLYING HOW METABOLIC REPROGRAMMING IMPACTS CARDIAC AGING IS THOUGHT TO CONTRIBUTE TO THE NOVEL INTERVENTIONS TO PROTECT OR EVEN RESTORE CARDIAC FUNCTION IN AGING HEARTS. HERE, WE SUMMARIZE EMERGING CONCEPTS ABOUT METABOLIC LANDSCAPES OF CARDIAC AGING, WITH SPECIFIC FOCUSES ON WHY METABOLIC PROFILE ALTERS DURING CARDIAC DEGENERATION AND HOW WE COULD UTILIZE THE CURRENT KNOWLEDGE TO IMPROVE THE MANAGEMENT OF CARDIAC AGING.	2023