1 2554 145 EPIGENETICS IN REACTIVE AND REPARATIVE CARDIAC FIBROGENESIS: THE PROMISE OF EPIGENETIC THERAPY. EPIGENETIC CHANGES PLAY A PIVOTAL ROLE IN THE DEVELOPMENT OF A WIDE SPECTRUM OF HUMAN DISEASES INCLUDING CARDIOVASCULAR DISEASES, CANCER, DIABETES, AND INTELLECTUAL DISABILITIES. CARDIAC FIBROGENESIS IS A COMMON PATHOPHYSIOLOGICAL PROCESS SEEN DURING CHRONIC AND STRESS-INDUCED ACCELERATED CARDIAC AGING. WHILE ADEQUATE PRODUCTION OF EXTRACELLULAR MATRIX (ECM) PROTEINS IS NECESSARY FOR POST-INJURY WOUND HEALING, EXCESSIVE SYNTHESIS AND ACCUMULATION OF EXTRACELLULAR MATRIX PROTEIN IN THE STRESSED OR INJURED HEARTS CAUSES DECREASED OR LOSS OF LUSITROPY THAT LEADS TO CARDIAC FAILURE. THIS SELF-PERPETUATING DEPOSITION OF COLLAGEN AND OTHER MATRIX PROTEINS EVENTUALLY ALTER CELLULAR HOMEOSTASIS; IMPAIR TISSUE ELASTICITY AND LEADS TO MULTI-ORGAN FAILURE, AS SEEN DURING PATHOGENESIS OF CARDIOVASCULAR DISEASES, CHRONIC KIDNEY DISEASES, CIRRHOSIS, IDIOPATHIC PULMONARY FIBROSIS, AND SCLERODERMA. IN THE LAST 25 YEARS, MULTIPLE STUDIES HAVE INVESTIGATED THE MOLECULAR BASIS OF ORGAN FIBROSIS AND HIGHLIGHTED ITS MULTI-FACTORIAL GENETIC, EPIGENETIC, AND ENVIRONMENTAL REGULATION. IN THIS MINIREVIEW, WE FOCUS ON FIVE MAJOR EPIGENETIC REGULATORS AND DISCUSS THEIR CENTRAL ROLE IN CARDIAC FIBROGENESIS. ADDITIONALLY, WE COMPARE AND CONTRAST THE EPIGENETIC REGULATION OF HYPERTENSION-INDUCED REACTIVE FIBROGENESIS AND MYOCARDIAL INFARCTION-INDUCED REPARATIVE OR REPLACEMENT CARDIAC FIBROGENESIS. AS MICRORNAS-ONE OF THE MAJOR EPIGENETIC REGULATORS-CIRCULATE IN PLASMA, WE ALSO ADVOCATE THEIR POTENTIAL DIAGNOSTIC ROLE IN CARDIAC FIBROSIS. LASTLY, WE DISCUSS THE EVOLUTION OF NOVEL EPIGENETIC-REGULATING DRUGS AND PREDICT THEIR CLINICAL ROLE IN THE SUPPRESSION OF PATHOLOGICAL CARDIAC REMODELING, CARDIAC AGING, AND HEART FAILURE. J. CELL. PHYSIOL. 232: 1941-1956, 2017. (C) 2016 WILEY PERIODICALS, INC. 2017 2 1597 47 DNA METHYLATION REGULATED GENE EXPRESSION IN ORGAN FIBROSIS. DNA METHYLATION IS A MAJOR EPIGENETIC MECHANISM TO REGULATE GENE EXPRESSION. EPIGENETIC REGULATION, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND RNA INTERFERENCE, RESULTS IN HERITABLE CHANGES IN GENE EXPRESSION INDEPENDENT OF ALTERATIONS IN DNA SEQUENCE. EPIGENETIC REGULATION OFTEN OCCURS IN RESPONSE TO AGING AND ENVIRONMENT STIMULI, INCLUDING EXPOSURES AND DIET. STUDIES HAVE SHOWN THAT DNA METHYLATION IS CRITICAL IN THE PATHOGENESIS OF FIBROSIS INVOLVING MULTIPLE ORGAN SYSTEMS, CONTRIBUTING TO SIGNIFICANT MORBIDITY AND MORTALITY. ABERRANT DNA METHYLATION CAN SILENCE OR ACTIVATE GENE EXPRESSION PATTERNS THAT DRIVE THE FIBROSIS PROCESS. FIBROSIS IS A PATHOLOGICAL WOUND HEALING PROCESS IN RESPONSE TO CHRONIC INJURY. IT IS CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX PRODUCTION AND ACCUMULATION, WHICH EVENTUALLY AFFECTS ORGAN ARCHITECTURE AND RESULTS IN ORGAN FAILURE. FIBROSIS CAN AFFECT A WIDE RANGE OF ORGANS, INCLUDING THE HEART AND LUNGS, AND HAVE LIMITED THERAPEUTIC OPTIONS. DNA METHYLATION, LIKE OTHER EPIGENETIC PROCESS, IS REVERSIBLE, THEREFORE REGARDED AS ATTRACTIVE THERAPEUTIC INTERVENTIONS. ALTHOUGH EPIGENETIC MECHANISMS ARE HIGHLY INTERACTIVE AND OFTEN REINFORCING, THIS REVIEW DISCUSSES DNA METHYLATION-DEPENDENT MECHANISMS IN THE PATHOGENESIS OF ORGAN FIBROSIS, WITH FOCUS ON CARDIAC AND PULMONARY FIBROSIS. WE DISCUSS SPECIFIC PRO- AND ANTI-FIBROTIC GENES AND PATHWAYS REGULATED BY DNA METHYLATION IN ORGAN FIBROSIS; WE FURTHER HIGHLIGHT THE POTENTIAL BENEFITS AND SIDE-EFFECTS OF EPIGENETIC THERAPIES IN FIBROTIC DISORDERS. 2017 3 4882 34 OVERVIEW OF THE CELLULAR AND MOLECULAR BASIS OF KIDNEY FIBROSIS. THE COMMON PATHOGENETIC PATHWAY OF PROGRESSIVE INJURY IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS EPITOMIZED AS NORMAL KIDNEY PARENCHYMAL DESTRUCTION DUE TO SCARRING (FIBROSIS). UNDERSTANDING THE FUNDAMENTAL PATHWAYS THAT LEAD TO RENAL FIBROSIS IS ESSENTIAL IN ORDER TO DEVELOP BETTER THERAPEUTIC OPTIONS FOR HUMAN CKD. ALTHOUGH COMPLEX, FOUR CELLULAR RESPONSES ARE PIVOTAL. (1) AN INTERSTITIAL INFLAMMATORY RESPONSE THAT HAS MULTIPLE CONSEQUENCES-SOME HARMFUL AND OTHERS HEALING. (2) THE APPEARANCE OF A UNIQUE INTERSTITIAL CELL POPULATION OF MYOFIBROBLASTS, PRIMARILY DERIVED FROM KIDNEY STROMAL CELLS (FIBROBLASTS AND PERICYTES), THAT ARE THE PRIMARY SOURCE OF THE VARIOUS EXTRACELLULAR MATRIX PROTEINS THAT FORM INTERSTITIAL SCARS. (3) TUBULAR EPITHELIAL CELLS THAT HAVE VARIABLE AND TIME-DEPENDENT ROLES AS EARLY RESPONDERS TO INJURY AND LATER AS VICTIMS OF FIBROSIS DUE TO THE LOSS OF THEIR REGENERATIVE ABILITIES. (4) LOSS OF INTERSTITIAL CAPILLARY INTEGRITY THAT COMPROMISES OXYGEN DELIVERY AND LEADS TO A VICIOUS CASCADE OF HYPOXIA-OXIDANT STRESS THAT ACCENTUATES INJURY AND FIBROSIS. IN THE ABSENCE OF ADEQUATE ANGIOGENIC RESPONSES, A HEALTHY INTERSTITIAL CAPILLARY NETWORK IS NOT MAINTAINED. THE FIBROTIC 'SCAR' THAT TYPIFIES CKD IS AN INTERESTING CONSORTIUM OF MULTIFUNCTIONAL MACROMOLECULES THAT NOT ONLY CHANGE IN COMPOSITION AND STRUCTURE OVER TIME, BUT CAN BE DEGRADED VIA EXTRACELLULAR AND INTRACELLULAR PROTEASES. ALTHOUGH TRANSFORMING GROWTH FACTOR BETA APPEARS TO BE THE PRIMARY DRIVER OF KIDNEY FIBROSIS, A VAST ARRAY OF ADDITIONAL MOLECULES MAY HAVE MODULATING ROLES. THE IMPORTANCE OF GENETIC AND EPIGENETIC FACTORS IS INCREASINGLY APPRECIATED. AN INTRIGUING BUT INCOMPLETELY UNDERSTOOD CARDIORENAL SYNDROME UNDERLIES THE HIGH MORBIDITY AND MORTALITY RATES THAT DEVELOP IN ASSOCIATION WITH PROGRESSIVE KIDNEY FIBROSIS. 2014 4 4191 40 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 5 3640 31 INCREASED EXTRACELLULAR MATRIX PROTEIN PRODUCTION IN CHRONIC DIABETIC COMPLICATIONS: IMPLICATIONS OF NON-CODING RNAS. MANAGEMENT OF CHRONIC DIABETIC COMPLICATIONS REMAINS A MAJOR MEDICAL CHALLENGE WORLDWIDE. ONE OF THE CHARACTERISTIC FEATURES OF ALL CHRONIC DIABETIC COMPLICATIONS IS AUGMENTED PRODUCTION OF EXTRACELLULAR MATRIX (ECM) PROTEINS. SUCH ECM PROTEINS ARE DEPOSITED IN ALL TISSUES AFFECTED BY CHRONIC COMPLICATIONS, ULTIMATELY CAUSING ORGAN DAMAGE AND DYSFUNCTION. A CONTRIBUTING FACTOR TO THIS PATHOGENETIC PROCESS IS GLUCOSE-INDUCED ENDOTHELIAL DAMAGE, WHICH INVOLVES PHENOTYPIC TRANSFORMATION OF ENDOTHELIAL CELLS (ECS). THIS PHENOTYPIC TRANSITION OF ECS, FROM A QUIESCENT STATE TO AN ACTIVATED DYSFUNCTIONAL STATE, CAN BE MEDIATED THROUGH ALTERATIONS IN THE SYNTHESIS OF CELLULAR PROTEINS. IN THIS REVIEW, WE DISCUSSED THE ROLES OF NON-CODING RNAS, SPECIFICALLY MICRORNAS (MIRNAS) AND LONG NON-CODING RNAS (LNCRNAS), IN SUCH PROCESSES. WE FURTHER OUTLINED OTHER EPIGENETIC MECHANISMS REGULATING THE BIOGENESIS AND/OR FUNCTION OF NON-CODING RNAS. OVERALL, WE BELIEVE THAT BETTER UNDERSTANDING OF SUCH MOLECULAR PROCESSES MAY LEAD TO THE DEVELOPMENT OF NOVEL BIOMARKERS AND THERAPEUTIC STRATEGIES IN THE FUTURE. 2019 6 5805 38 STRATEGIES TO PREVENT AND REVERSE LIVER FIBROSIS IN HUMANS AND LABORATORY ANIMALS. LIVER FIBROSIS RESULTS FROM CHRONIC DAMAGE TO THE LIVER IN CONJUNCTION WITH VARIOUS PATHWAYS AND IS MEDIATED BY A COMPLEX MICROENVIRONMENT. BASED ON CLINICAL OBSERVATIONS, IT IS NOW EVIDENT THAT FIBROSIS IS A DYNAMIC, BIDIRECTIONAL PROCESS WITH AN INHERENT CAPACITY FOR RECOVERY AND REMODELING. THE MAJOR MECHANISMS INVOLVED IN LIVER FIBROSIS INCLUDE THE REPETITIVE INJURY OF HEPATOCYTES, THE ACTIVATION OF THE INFLAMMATORY RESPONSE AFTER INJURY STIMULATION, AND THE ACTIVATION AND PROLIFERATION OF HEPATIC STELLATE CELLS (HSCS), WHICH REPRESENTS THE MAJOR EXTRACELLULAR MATRIX (ECM)-PRODUCING CELLS, STIMULATED BY HEPATOCYTE INJURY AND INFLAMMATION. THE MICROENVIRONMENT IN THE LIVER IS SYNERGISTICALLY REGULATED ABNORMAL ECM DEPOSITION, SCAR FORMATION, ANGIOGENESIS, AND FIBROGENESIS. MOREOVER, RECENT STUDIES HAVE CLARIFIED NOVEL MECHANISM IN FIBROSIS SUCH AS EPIGENETIC REGULATION OF HSCS, THE LEPTIN AND PPARGAMMA PATHWAYS, THE COAGULATION SYSTEM, AND EVEN AUTOPHAGY. UNCOVERING THE MECHANISMS OF LIVER FIBROGENESIS PROVIDES A BASIS TO DEVELOP POTENTIAL THERAPIES TO REVERSE AND TREAT THE FIBROTIC RESPONSE, THEREBY IMPROVING THE OUTCOMES OF PATIENTS WITH CHRONIC LIVER DISEASE. ALTHOUGH BOTH SCIENTIFIC AND CLINICAL CHALLENGES REMAIN, EMERGING STUDIES ATTEMPT TO REVEAL THE IDEAL ANTI-FIBROTIC DRUG THAT COULD BE EASILY DELIVERED TO THE LIVER WITH HIGH SPECIFICITY AND LOW TOXICITY. THIS REVIEW HIGHLIGHTS THE MECHANISMS, INCLUDING NOVEL PATHWAYS UNDERLYING FIBROGENESIS THAT MAY BE TRANSLATED INTO PREVENTIVE AND TREATMENT STRATEGIES, REVIEWS BOTH CURRENT AND NOVEL AGENTS THAT TARGET SPECIFIC PATHWAYS OR MULTIPLE TARGETS, AND DISCUSSES NOVEL DRUG DELIVERY SYSTEMS SUCH AS NANOTECHNOLOGY THAT CAN BE APPLIED IN THE TREATMENT OF LIVER FIBROSIS. IN ADDITION, WE ALSO DISCUSS SOME CURRENT TREATMENT STRATEGIES THAT ARE BEING APPLIED IN ANIMAL MODELS AND IN CLINICAL TRIALS. 2015 7 5660 31 SEX-SPECIFIC EPIGENETIC PROGRAMMING IN RENAL FIBROSIS AND INFLAMMATION. THE GROWING PREVALENCE OF HYPERTENSION, HEART DISEASE, DIABETES, AND OBESITY ALONG WITH AN AGING POPULATION, IS LEADING TO HIGHER INCIDENCE OF RENAL DISEASES IN THE SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED MAINLY BY PERSISTENT INFLAMMATION, FIBROSIS, AND GRADUAL LOSS OF RENAL FUNCTION LEADING TO RENAL FAILURE. SEX IS A KNOWN CONTRIBUTOR TO THE DIFFERENCES IN INCIDENCE AND PROGRESSION OF CKD. EPIGENETIC PROGRAMMING IS AN ESSENTIAL REGULATOR OF RENAL PHYSIOLOGY AND IS CRITICALLY INVOLVED IN THE PATHOPHYSIOLOGY OF RENAL INJURY AND FIBROSIS. EPIGENETIC SIGNALING INTEGRATES INTRINSIC AND EXTRINSIC SIGNALS ONTO THE GENOME, AND VARIOUS ENVIRONMENTAL AND HORMONAL STIMULI, INCLUDING SEX HORMONES, WHICH REGULATE GENE EXPRESSION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST EXTENSIVELY STUDIED EPIGENETIC ALTERATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE HISTONE MODIFICATIONS AND DNA METHYLATION. NOTABLY, THESE EPIGENETIC ALTERATIONS ARE REVERSIBLE, MAKING THEM CANDIDATES FOR POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OF RENAL DISEASES. HERE, WE WILL SUMMARIZE THE CURRENT KNOWLEDGE ON SEX-DIFFERENCES IN EPIGENETIC MODULATION OF RENAL FIBROSIS AND INFLAMMATION AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2023 8 6223 33 THE LEADING ROLE OF EPITHELIAL CELLS IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A RELENTLESSLY PROGRESSIVE AND DEVASTATING INTERSTITIAL LUNG DISEASE OF UNKNOWN ETIOLOGY, WHERE THE NORMAL LUNG ARCHITECTURE IS LOST AND REPLACED BY FIBROTIC TISSUE LEADING TO AN IRREVERSIBLE AND PROGRESSIVE RESPIRATORY INSUFFICIENCY. HISTORICALLY, IPF WAS CONSIDERED A CHRONIC INFLAMMATORY DISORDER, WHICH GRADUALLY PROGRESSED TO ESTABLISHED FIBROSIS. HOWEVER, STRONG CLINICAL AND EXPERIMENTAL EVIDENCE INDICATES THAT THE DISEASE REPRESENTS AN EPITHELIAL-DRIVEN DISORDER WHICH RESULTS FROM A COMPLEX INTERPLAY OF GENETIC AND ENVIRONMENTAL RISK FACTORS, AGING-ASSOCIATED PROCESSES AND A PROFIBROTIC EPIGENETIC REPROGRAMMING. THE CONVERGENCE OF THESE FACTORS RESULTS IN THE ABERRANT ACTIVATION OF EPITHELIAL CELLS THAT INITIATE THE DEVELOPMENT OF THE DISEASE, PRODUCING VIRTUALLY ALL THE MEDIATORS THAT PARTICIPATE IN THE MIGRATION, PROLIFERATION AND ACTIVATION OF FIBROBLASTS, THEIR DIFFERENTIATION TO MYOFIBROBLASTS AND THE EXCESSIVE AND CHAOTIC SECRETION OF EXTRACELLULAR MATRIX PROTEINS. ALTHOUGH PROGRESS HAS BEEN MADE IN UNDERSTANDING THE CAUSES AND CONSEQUENCES OF THIS ABNORMAL BEHAVIOR OF DISTAL AIRWAYS AND ALVEOLAR EPITHELIUM, THE MECHANISMS THAT INITIATE AND PERPETUATE THE VICIOUS CIRCLE OF MULTIDIRECTIONAL ABNORMAL COMMUNICATIONS BETWEEN THE EPITHELIUM AND FIBROBLASTS AND OTHER RESIDENT CELLS HAVE NOT BEEN ELUCIDATED. IN THIS REVIEW, WE DISCUSS THE ROLE OF EPITHELIAL CELLS AND THE MECHANISMS UNDERLYING THE FIBROTIC RESPONSE IN IPF, AND HIGHLIGHT SOME PROMISING THERAPEUTIC TARGETS FOR THESE CELLS. 2020 9 2343 30 EPIGENETIC REGULATION OF MACROPHAGE POLARIZATION IN CARDIOVASCULAR DISEASES. CARDIOVASCULAR DISEASES (CVDS) ARE THE LEADING CAUSE OF HOSPITALIZATION AND DEATH WORLDWIDE, ESPECIALLY IN DEVELOPING COUNTRIES. THE INCREASED PREVALENCE RATE AND MORTALITY DUE TO CVDS, DESPITE THE DEVELOPMENT OF SEVERAL APPROACHES FOR PREVENTION AND TREATMENT, ARE ALARMING TRENDS IN GLOBAL HEALTH. CHRONIC INFLAMMATION AND MACROPHAGE INFILTRATION ARE KEY REGULATORS OF THE INITIATION AND PROGRESSION OF CVDS. RECENT DATA SUGGEST THAT EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, POSTTRANSLATIONAL HISTONE MODIFICATIONS, AND RNA MODIFICATIONS, REGULATE CELL DEVELOPMENT, DNA DAMAGE REPAIR, APOPTOSIS, IMMUNITY, CALCIUM SIGNALING, AND AGING IN CARDIOMYOCYTES; AND ARE INVOLVED IN MACROPHAGE POLARIZATION AND CONTRIBUTE SIGNIFICANTLY TO CARDIAC DISEASE DEVELOPMENT. CARDIAC MACROPHAGES NOT ONLY TRIGGER DAMAGING INFLAMMATORY RESPONSES DURING ATHEROSCLEROTIC PLAQUE FORMATION, MYOCARDIAL INJURY, AND HEART FAILURE BUT ARE ALSO INVOLVED IN TISSUE REPAIR, REMODELING, AND REGENERATION. IN THIS REVIEW, WE SUMMARIZE THE KEY EPIGENETIC MODIFICATIONS THAT INFLUENCE MACROPHAGE POLARIZATION AND CONTRIBUTE TO THE PATHOPHYSIOLOGY OF CVDS, AND HIGHLIGHT THEIR POTENTIAL FOR THE DEVELOPMENT OF ADVANCED EPIGENETIC THERAPIES. 2023 10 2933 39 GENESIS OF THE MYOFIBROBLAST IN LUNG INJURY AND FIBROSIS. TISSUE INJURY INCITES A REPAIR RESPONSE WITH A KEY MESENCHYMAL COMPONENT THAT PROVIDES THE ESSENTIAL CONNECTIVE TISSUE FOR SUBSEQUENT REGENERATION OR PATHOLOGICAL FIBROSIS. THE FIBROBLAST IS THE MAJOR MESENCHYMAL CELL TYPE TO BE IMPLICATED IN THIS CONNECTIVE TISSUE RESPONSE, AND IT IS IN ITS ACTIVATED OR DIFFERENTIATED FORM THAT IT PARTICIPATES IN THE REPAIR PROCESS. THE MYOFIBROBLAST REPRESENTS SUCH AN ACTIVATED MESENCHYMAL CELL AND IS A KEY SOURCE OF EXTRACELLULAR MATRIX AND INFLAMMATORY/FIBROGENIC CYTOKINES AS WELL AS PARTICIPATING IN WOUND CONTRACTION. ALTHOUGH SUCCESSFUL HEALING RESULTS IN GRADUAL DISAPPEARANCE OF MYOFIBROBLASTS, THEIR PERSISTENCE IS ASSOCIATED WITH CHRONIC AND PROGRESSIVE FIBROSIS. THUS, ELUCIDATION OF THE MECHANISM INVOLVED IN THE GENESIS OF THE MYOFIBROBLAST SHOULD PROVIDE INSIGHT INTO BOTH PATHOGENESIS OF CHRONIC FIBROTIC DISEASES AND THERAPEUTIC STRATEGIES FOR THEIR MANAGEMENT AND CONTROL. ALTHOUGH THE FIBROBLAST IS A WELL-DOCUMENTED PROGENITOR CELL FOR THE MYOFIBROBLAST, RECENT STUDIES HAVE SUGGESTED ADDITIONAL PRECURSOR CELLS THAT HAVE THE POTENTIAL TO GIVE RISE TO THE MYOFIBROBLAST. MANY OF THE STUDIES FOCUSED ON MECHANISMS AND FACTORS THAT REGULATE INDUCTION OF ALPHA-SMOOTH MUSCLE ACTIN EXPRESSION, A KEY AND COMMONLY USED MARKER OF THE MYOFIBROBLAST. THESE REVEAL COMPLEX AND MULTIFACTORIAL MECHANISMS INVOLVING TRANSCRIPTIONAL AND EPIGENETIC REGULATION AND IMPLICATING DIVERSE CELL-SIGNALING PATHWAYS, INCLUDING THOSE ACTIVATED BY THE POTENT FIBROGENIC CYTOKINE TRANSFORMING GROWTH FACTOR BETA. DESPITE THESE EXTENSIVE STUDIES, MANY ASPECTS REMAIN POORLY UNDERSTOOD, WITH THE SUGGESTION THAT ADDITIONAL NOVEL MECHANISMS REMAIN TO BE DISCOVERED. FUTURE STUDIES WITH THE HELP OF NEWLY DEVELOPED TECHNICAL ADVANCEMENTS SHOULD EXPEDITE DISCOVERY IN THIS DIRECTION. 2012 11 2283 32 EPIGENETIC REGULATION IN FIBROSIS PROGRESS. FIBROSIS, A COMMON PROCESS OF CHRONIC INFLAMMATORY DISEASES, IS DEFINED AS A REPAIR RESPONSE DISORDER WHEN ORGANS UNDERGO CONTINUOUS DAMAGE, ULTIMATELY LEADING TO SCAR FORMATION AND FUNCTIONAL FAILURE. AROUND THE WORLD, FIBROTIC DISEASES CAUSE HIGH MORTALITY, UNFORTUNATELY, WITH LIMITED TREATMENT MEANS IN CLINICAL PRACTICE. WITH THE DEVELOPMENT AND APPLICATION OF DEEP SEQUENCING TECHNOLOGY, COMPREHENSIVELY EXPLORING THE EPIGENETIC MECHANISM IN FIBROSIS HAS BEEN ALLOWED. EXTENSIVE REMODELING OF EPIGENETICS CONTROLLING VARIOUS CELLS PHENOTYPE AND MOLECULAR MECHANISMS INVOLVED IN FIBROGENESIS WAS SUBSEQUENTLY VERIFIED. IN THIS REVIEW, WE SUMMARIZE THE REGULATORY MECHANISMS OF DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNAS (NCRNAS) AND N6-METHYLADENOSINE (M6A) MODIFICATION IN ORGAN FIBROSIS, FOCUSING ON HEART, LIVER, LUNG AND KIDNEY. ADDITIONALLY, WE EMPHASIZE THE DIVERSITY OF EPIGENETICS IN THE CELLULAR AND MOLECULAR MECHANISMS RELATED TO FIBROSIS. FINALLY, THE POTENTIAL AND PROSPECT OF TARGETED THERAPY FOR FIBROSIS BASED ON EPIGENETIC IS DISCUSSED. 2021 12 4738 34 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 13 5801 30 STIFFNESS AND AGING IN CARDIOVASCULAR DISEASES: THE DANGEROUS RELATIONSHIP BETWEEN FORCE AND SENESCENCE. BIOLOGICAL AGING IS A PROCESS ASSOCIATED WITH A GRADUAL DECLINE IN TISSUES' HOMEOSTASIS BASED ON THE PROGRESSIVE INABILITY OF THE CELLS TO SELF-RENEW. CELLULAR SENESCENCE IS ONE OF THE HALLMARKS OF THE AGING PROCESS, CHARACTERIZED BY AN IRREVERSIBLE CELL CYCLE ARREST DUE TO REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, TELOMERES SHORTENING, CHRONIC INFLAMMATORY ACTIVATION, AND CHROMATIN MODIFICATIONS. IN THIS REVIEW, WE WILL DESCRIBE THE EFFECTS OF SENESCENCE ON TISSUE STRUCTURE, EXTRACELLULAR MATRIX (ECM) ORGANIZATION, AND NUCLEUS ARCHITECTURE, AND SEE HOW THESE CHANGES AFFECT (ARE AFFECTED BY) MECHANO-TRANSDUCTION. IN OUR VIEW, THIS IS ESSENTIAL FOR A DEEPER UNDERSTANDING OF THE PROGRESSIVE PATHOLOGICAL EVOLUTION OF THE CARDIOVASCULAR SYSTEM AND ITS RELATIONSHIP WITH THE DETRIMENTAL EFFECTS OF RISK FACTORS, KNOWN TO ACT AT AN EPIGENETIC LEVEL. 2021 14 5258 25 PROGRESSION OF TUBULOINTERSTITIAL FIBROSIS AND THE CHRONIC KIDNEY DISEASE PHENOTYPE - ROLE OF RISK FACTORS AND EPIGENETICS. ALTHOUGH THE KIDNEY HAS CAPACITY TO REPAIR AFTER MILD INJURY, ONGOING OR SEVERE DAMAGE RESULTS IN SCARRING (FIBROSIS) AND AN ASSOCIATED PROGRESSIVE LOSS OF KIDNEY FUNCTION. HOWEVER, DESPITE ITS UNIVERSAL SIGNIFICANCE, EVIDENCE HIGHLIGHTS A POPULATION BASED HETEROGENEITY IN THE TRAJECTORY OF CHRONIC KIDNEY DISEASE (CKD) IN THESE PATIENTS. TO EXPLAIN THE HETEROGENEITY OF THE CKD PHENOTYPE REQUIRES AN UNDERSTANDING OF THE RELEVANT RISK FACTORS FOR FIBROSIS. THESE FACTORS INCLUDE BOTH THE EXTRINSIC NATURE OF INJURY, AND INTRINSIC FACTORS SUCH AS AGE, GENDER, GENETICS, AND PERPETUAL ACTIVATION OF FIBROBLASTS THROUGH PRIMING. IN MANY CASES AN ADDITIONAL LEVEL OF REGULATION IS PROVIDED BY EPIGENETIC MECHANISMS WHICH INTEGRATE THE VARIOUS PRO-FIBROTIC AND ANTI-FIBROTIC TRIGGERS IN FIBROGENESIS. IN THIS REVIEW WE THEREFORE EXAMINE THE VARIOUS MOLECULAR AND STRUCTURAL CHANGES OF FIBROSIS, AND HOW THEY ARE INFLUENCED BY EXTRINSIC AND INTRINSIC FACTORS. OUR AIM IS TO PROVIDE A UNIFYING HYPOTHESIS TO HELP EXPLAIN THE TRANSITION FROM ACUTE TO CKD. 2017 15 2218 35 EPIGENETIC MODIFICATIONS IN FIBROTIC DISEASES: IMPLICATIONS FOR PATHOGENESIS AND PHARMACOLOGICAL TARGETS. ORGAN FIBROSIS IS A COMPLEX AND CHRONIC DISORDER THAT RESULTS FROM A VARIETY OF ACUTE INJURIES AND CONTRIBUTES TO THIRTY PERCENT OF NATURALLY OCCURRING DEATHS WORLDWIDE. THE MAIN FEATURE OF ORGAN FIBROSIS IS THE EXCESSIVE ACCUMULATION AND DEPOSIT OF EXTRACELLULAR MATRIX, THEREBY LEADING TO ORGAN DYSFUNCTION, LOSS OF ELASTICITY, AND DEVELOPMENT OF A RIGID ORGAN. ACCUMULATING EVIDENCE SHOWS THAT EPIGENETIC REMODELING, INCLUDING ABERRANT DNA METHYLATION AND NONCODING RNA EXPRESSION AS WELL AS HISTONE POST-TRANSLATIONAL MODIFICATIONS, PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF FIBROSIS THROUGH THE REGULATION OF FIBROBLAST ACTIVATION, DIFFERENTIATION, AND APOPTOSIS, AS WELL AS COLLAGEN SYNTHESIS AND PROFIBROTIC GENE TRANSCRIPTION. IN THIS REVIEW, WE DISCUSS THE BASIC REGULATION OF DNA METHYLATION, NONCODING RNA EXPRESSION, AND HISTONE POST-TRANSLATIONAL MODIFICATION, AND THEIR PARTICIPATION IN THE PATHOGENESIS AND DEVELOPMENT OF ORGAN FIBROSIS. THIS REVIEW ALSO PROVIDES THE LATEST INSIGHTS INTO THE NOVEL BIOMARKERS AND THERAPEUTIC TARGETS FOR FIBROSIS THROUGH MODULATION OF EPIGENETIC REMODELING. 2015 16 2609 33 EPIGENETICS: A POTENTIAL KEY MECHANISM INVOLVED IN THE PATHOGENESIS OF CARDIORENAL SYNDROMES. EPIGENETICS IS DEFINED AS THE HERITABLE CHANGES IN GENE EXPRESSION PATTERNS WHICH ARE NOT DIRECTLY ENCODED BY MODIFICATIONS IN THE NUCLEOTIDE DNA SEQUENCE OF THE GENOME, INCLUDING HIGHER ORDER CHROMATIN ORGANIZATION, DNA METHYLATION, CYTOSINE MODIFICATIONS, COVALENT HISTONE TAIL MODIFICATIONS, AND SHORT NON-CODING RNA MOLECULES. RECENTLY, MUCH ATTENTION HAS BEEN PAID TO THE ROLE AND THE FUNCTION OF EPIGENETICS AND EPIMUTATIONS IN THE CELLULAR AND SUBCELLULAR PATHWAYS AND IN THE REGULATION OF GENES IN THE SETTING OF BOTH KIDNEY AND CARDIOVASCULAR DISEASE. INDEED, DEREGULATION OF HISTONE ALTERATIONS HAS BEEN HIGHLIGHTED IN A LARGE SPECTRUM OF RENAL AND CARDIAC DISEASE, INCLUDING CHRONIC AND ACUTE RENAL INJURY, RENAL AND CARDIAC FIBROSIS, CARDIAC HYPERTROPHY AND FAILURE, KIDNEY CONGENITAL ANOMALIES, RENAL HYPOXIA, AND DIABETIC RENAL COMPLICATIONS. NEVERTHELESS, THE ROLE OF EPIGENETICS IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF CARDIORENAL SYNDROMES IS CURRENTLY UNDEREXPLORED. GIVEN THE SIGNIFICANT CLINICAL RELEVANCE OF HEART-KIDNEY CROSSTALK, EFFORTS IN THE RESEARCH FOR NEW ACTION MECHANISMS CONCURRENTLY OPERATING IN BOTH PATHOLOGIES ARE THUS OF MAXIMUM INTEREST. THIS REVIEW FOCUSES ON EPIGENETIC MECHANISMS INVOLVED IN HEART AND KIDNEY DISEASE, AND THEIR POSSIBLE ROLE IN THE SETTING OF CARDIORENAL SYNDROMES. 2018 17 4980 40 PATHOPHYSIOLOGY OF LIVER FIBROSIS. PROGRESSIVE ACCUMULATION OF FIBRILLAR EXTRACELLULAR MATRIX (ECM) IN THE LIVER IS THE CONSEQUENCE OF REITERATED LIVER TISSUE DAMAGE DUE TO INFECTIVE (MOSTLY HEPATITIS B AND C VIRUSES), TOXIC/DRUG-INDUCED, METABOLIC AND AUTOIMMUNE CAUSES, AND THE RELATIVE CHRONIC ACTIVATION OF THE WOUND-HEALING REACTION. THE PROCESS MAY RESULT IN CLINICALLY EVIDENT LIVER CIRRHOSIS AND HEPATIC FAILURE. ALTHOUGH CIRRHOSIS IS THE COMMON RESULT OF PROGRESSIVE FIBROGENESIS, THERE ARE DISTINCT PATTERNS OF FIBROTIC DEVELOPMENT RELATED TO THE UNDERLYING DISORDERS CAUSING THE FIBROSIS. THESE DIFFERENT PATTERNS OF FIBROGENIC EVOLUTION ARE RELATED TO DIFFERENT FACTORS AND PARTICULARLY: (1) THE TOPOGRAPHIC LOCALIZATION OF TISSUE DAMAGE, (2) THE RELATIVE CONCENTRATION OF PROFIBROGENIC FACTORS AND (3) THE PREVALENT PROFIBROGENIC MECHANISM(S). THE MECHANISMS RESPONSIBLE FOR THE FIBROGENIC EVOLUTION OF CHRONIC LIVER DISEASES CAN BE SUMMARIZED IN THREE MAIN GROUPS: CHRONIC ACTIVATION OF THE WOUND-HEALING REACTION, OXIDATIVE STRESS-RELATED MOLECULAR MECHANISMS, AND THE DERANGEMENT OF THE SO-CALLED 'EPITHELIAL-MESENCHYMAL' INTERACTION LEADING TO THE GENERATION OF REACTIVE CHOLANGIOCYTES AND PERIBILIARY FIBROSIS. MOST OF THE KNOWLEDGE ON THE CELL AND MOLECULAR BIOLOGY OF HEPATIC FIBROSIS DERIVES FROM IN VITRO STUDIES EMPLOYING CULTURE OF ACTIVATED HEPATIC STELLATE CELLS ISOLATED FROM RAT, MOUSE OR HUMAN LIVER. IT IS NOW EVIDENT THAT OTHER ECM-PRODUCING CELLS, I.E. FIBROBLASTS AND MYOFIBROBLASTS OF THE PORTAL TRACT AND CIRCULATING 'FIBROCYTES', ARE LIKELY TO CONTRIBUTE TO LIVER FIBROSIS. MORE RECENTLY, THE ATTENTION IS PROGRESSIVELY SHIFTING TO THE PROFIBROTIC MICROENVIRONMENT OF THE LIVER WITH INCREASING INTEREST FOR THE ROLE OF IMMUNE CELLS AND SPECIFIC SUBSETS OF MACROPHAGES REGULATING THE PROGRESSION OR THE REGRESSION OF FIBROSIS, THE ROLE OF INTESTINAL MICROBIOTA AND THE INFLUENCE OF TISSUE STIFFNESS. OTHER MAJOR AREAS OF DEVELOPMENT INCLUDE THE ROLE OF TISSUE HYPOXIA AND THE ESTABLISHMENT OF AN ANAEROBIC PROINFLAMMATORY ENVIRONMENT AND THE INFLUENCE OF EPIGENETIC MODIFICATION IN CONDITIONING THE PROGRESSION OF FIBROSIS. 2015 18 2381 30 EPIGENETIC REGULATION OF WOUND HEALING AND FIBROSIS. PURPOSE OF REVIEW: WOUND HEALING IS A NORMAL PHYSIOLOGICAL RESPONSE TO TISSUE INJURY WHICH CAN OCCUR IN ANY ORGAN. MECHANISMS THAT ORCHESTRATE WOUND HEALING IN DIFFERENT ORGANS ARE SURPRISINGLY GENERIC, INVOLVING GENERATION OF FIBROBLASTS AND MYOFIBROBLASTS BY DIFFERENTIATION PROCESSES THAT REQUIRE EXTENSIVE ALTERATIONS IN GENE EXPRESSION. THIS PROCESS AND INDEED PHENOTYPE OF CELLS ARE ORCHESTRATED BY THE COMBINED INFLUENCES OF MOLECULAR COMPONENTS OF EPIGENOME INCLUDING DNA METHYLATION, VAST ARRAY OF POSTTRANSLATIONAL MODIFICATIONS OF THE HISTONE PROTEIN CONSTITUENTS OF CHROMATIN AND REGULATORY NONCODING RNAS OF WHICH MICRORNAS (MIRS) ARE THE MOST EXTENSIVELY STUDIED. RECENT FINDINGS: NUMEROUS STUDIES FROM THE LAST 12 MONTHS SHOW ALL THE THREE EPIGENETIC MECHANISMS TO BE REGULATING GENERATION AND APOPTOSIS OF MYOFIBROBLASTS IN ORGANS AFFECTED BY PERTURBED WOUND HEALING. FURTHERMORE, THESE MECHANISMS ARE INVOLVED IN FIBROTIC DISEASE ITSELF, WITH SOME MIRS AND EPIGENETIC DRUGS BEING TESTED FOR THEIR THERAPEUTIC POTENTIAL. SUMMARY: FIELDS OF WOUND HEALING AND FIBROSIS WILL BE ENRICHED OVER THE NEXT DECADE BY PLETHORA OF NEW INFORMATION REGARDING EPIGENETIC CONTROL MECHANISMS WHICH WILL HOPEFULLY PROVIDE NEW ADVANCES IN DIAGNOSTICS AND PROGNOSTICS. WITH THE DESIGN OF EVER MORE SPECIFIC EPIGENETIC DRUGS, WE MAY IMPROVE OUR ABILITY TO THERAPEUTICALLY OPTIMIZE WOUND HEALING AND PREVENT FIBROSIS IN CHRONIC DISEASE AND AGEING. 2013 19 607 29 BEYOND GENETICS: EPIGENETIC CODE IN CHRONIC KIDNEY DISEASE. EPIGENETICS REFERS TO A HERITABLE CHANGE IN THE PATTERN OF GENE EXPRESSION THAT IS MEDIATED BY A MECHANISM SPECIFICALLY NOT DUE TO ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. WELL-KNOWN EPIGENETIC MECHANISMS ENCOMPASS DNA METHYLATION, CHROMATIN REMODELING (HISTONE MODIFICATIONS), AND RNA INTERFERENCE. FUNCTIONALLY, EPIGENETICS PROVIDES AN EXTRA LAYER OF TRANSCRIPTIONAL CONTROL AND PLAYS A CRUCIAL ROLE IN NORMAL PHYSIOLOGICAL DEVELOPMENT, AS WELL AS IN PATHOLOGICAL CONDITIONS. ABERRANT DNA METHYLATION IS IMPLICATED IN IMMUNE DYSFUNCTION, INFLAMMATION, AND INSULIN RESISTANCE. EPIGENETIC CHANGES MAY BE RESPONSIBLE FOR 'METABOLIC MEMORY' AND DEVELOPMENT OF MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES. MICRORNAS ARE CRITICAL IN THE MAINTENANCE OF GLOMERULAR HOMEOSTASIS AND HENCE RNA INTERFERENCE MAY BE IMPORTANT IN THE PROGRESSION OF RENAL DISEASE. RECENT STUDIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS ORCHESTRATE THE EPITHELIAL-MESENCHYMAL TRANSITION AND EVENTUALLY FIBROSIS OF THE RENAL TISSUE. OXIDATIVE STRESS, INFLAMMATION, HYPERHOMOCYSTEINEMIA, AND UREMIC TOXINS COULD INDUCE EPIMUTATIONS IN CHRONIC KIDNEY DISEASE. EPIGENETIC ALTERATIONS ARE ASSOCIATED WITH INFLAMMATION AND CARDIOVASCULAR DISEASE IN PATIENTS WITH CHRONIC KIDNEY DISEASE. REVERSIBLE NATURE OF THE EPIGENETIC CHANGES GIVES A UNIQUE OPPORTUNITY TO HALT OR EVEN REVERSE THE DISEASE PROCESS THROUGH TARGETED THERAPEUTIC STRATEGIES. 2011 20 5933 34 TARGETING EPIGENETICS AND NON-CODING RNAS IN ATHEROSCLEROSIS: FROM MECHANISMS TO THERAPEUTICS. ATHEROSCLEROSIS, THE PRINCIPAL CAUSE OF CARDIOVASCULAR DEATH WORLDWIDE, IS A PATHOLOGICAL DISEASE CHARACTERIZED BY FIBRO-PROLIFERATION, CHRONIC INFLAMMATION, LIPID ACCUMULATION, AND IMMUNE DISORDER IN THE VESSEL WALL. AS THE ATHEROMATOUS PLAQUES DEVELOP INTO ADVANCED STAGE, THE VULNERABLE PLAQUES ARE PRONE TO RUPTURE, WHICH CAUSES ACUTE CARDIOVASCULAR EVENTS, INCLUDING ISCHEMIC STROKE AND MYOCARDIAL INFARCTION. EMERGING EVIDENCE HAS SUGGESTED THAT ATHEROSCLEROSIS IS ALSO AN EPIGENETIC DISEASE WITH THE INTERPLAY OF MULTIPLE EPIGENETIC MECHANISMS. THE EPIGENETIC BASIS OF ATHEROSCLEROSIS HAS TRANSFORMED OUR KNOWLEDGE OF EPIGENETICS FROM AN IMPORTANT BIOLOGICAL PHENOMENON TO A BURGEONING FIELD IN CARDIOVASCULAR RESEARCH. HERE, WE PROVIDE A SYSTEMATIC AND UP-TO-DATE OVERVIEW OF THE CURRENT KNOWLEDGE OF THREE DISTINCT BUT INTERRELATED EPIGENETIC PROCESSES (INCLUDING DNA METHYLATION, HISTONE METHYLATION/ACETYLATION, AND NON-CODING RNAS), IN ATHEROSCLEROTIC PLAQUE DEVELOPMENT AND INSTABILITY. MECHANISTIC AND CONCEPTUAL ADVANCES IN UNDERSTANDING THE BIOLOGICAL ROLES OF VARIOUS EPIGENETIC MODIFIERS IN REGULATING GENE EXPRESSION AND FUNCTIONS OF ENDOTHELIAL CELLS (VASCULAR HOMEOSTASIS, LEUKOCYTE ADHESION, ENDOTHELIAL-MESENCHYMAL TRANSITION, ANGIOGENESIS, AND MECHANOTRANSDUCTION), SMOOTH MUSCLE CELLS (PROLIFERATION, MIGRATION, INFLAMMATION, HYPERTROPHY, AND PHENOTYPIC SWITCH), AND MACROPHAGES (DIFFERENTIATION, INFLAMMATION, FOAM CELL FORMATION, AND POLARIZATION) ARE DISCUSSED. THE INHERENTLY DYNAMIC NATURE AND REVERSIBILITY OF EPIGENETIC REGULATION, ENABLES THE POSSIBILITY OF EPIGENETIC THERAPY BY TARGETING EPIGENETIC "WRITERS", "READERS", AND "ERASERS". SEVERAL FOOD DRUG ADMINISTRATION-APPROVED SMALL-MOLECULE EPIGENETIC DRUGS SHOW PROMISE IN PRE-CLINICAL STUDIES FOR THE TREATMENT OF ATHEROSCLEROSIS. FINALLY, WE DISCUSS POTENTIAL THERAPEUTIC IMPLICATIONS AND CHALLENGES FOR FUTURE RESEARCH INVOLVING CARDIOVASCULAR EPIGENETICS, WITH AN AIM TO PROVIDE A TRANSLATIONAL PERSPECTIVE FOR IDENTIFYING NOVEL BIOMARKERS OF ATHEROSCLEROSIS, AND TRANSFORMING PRECISION CARDIOVASCULAR RESEARCH AND DISEASE THERAPY IN MODERN ERA OF EPIGENETICS. 2019