1 6214 140 THE INTRACELLULAR SIGNALING PATHWAYS GOVERNING MACROPHAGE ACTIVATION AND FUNCTION IN HUMAN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY LIPID ACCUMULATION AND PLAQUE FORMATION IN ARTERIAL VESSEL WALLS. ATHEROSCLEROTIC PLAQUES NARROW THE ARTERIAL LUMEN TO INCREASE THE RISK OF HEART ATTACKS, ISCHEMIC STROKE AND PERIPHERAL VASCULAR DISEASE, WHICH ARE MAJOR AND WORLDWIDE HEALTH AND ECONOMIC BURDENS. MACROPHAGE ACCUMULATION WITHIN PLAQUES IS CHARACTERISTIC OF ALL STAGES OF ATHEROSCLEROSIS AND THEIR PRESENCE IS A POTENTIAL MARKER OF DISEASE ACTIVITY AND PLAQUE STABILITY. MACROPHAGES ENGULF LIPIDS AND MODIFIED LIPOPROTEINS TO FORM FOAM CELLS THAT EXPRESS PRO-INFLAMMATORY AND CHEMOTACTIC EFFECTOR MOLECULES, STRESS INDUCING FACTORS AND REACTIVE OXYGEN SPECIES. THEY CONTROL PLAQUE STABILITY AND RUPTURE THROUGH SECRETION OF METALLOPROTEINASES AND EXTRACELLULAR MATRIX DEGRADATION. ALTHOUGH MACROPHAGES CAN WORSEN DISEASE BY PROPAGATING INFLAMMATION, THEY CAN STABILIZE ATHEROSCLEROTIC PLAQUES THROUGH TISSUE REMODELING, PROMOTING THE FORMATION OF A FIBROUS CAP, CLEARING APOPTOTIC CELLS TO PREVENT NECROTIC CORE FORMATION AND THROUGH VASCULAR REPAIR. IN ATHEROSCLEROSIS, MACROPHAGES RESPOND TO DYSLIPIDAEMIA, CYTOKINES, DYING CELLS, METABOLIC FACTORS, LIPIDS, PHYSICAL STIMULI AND EPIGENETIC FACTORS AND EXHIBIT HETEROGENEITY IN THEIR ACTIVATION DEPENDING ON THE STIMULI THEY RECEIVE. UNDERSTANDING THESE SIGNALS AND THE PATHWAYS DRIVING MACROPHAGE FUNCTION WITHIN DEVELOPING AND ESTABLISHED PLAQUES AND HOW THEY CAN BE PHARMACOLOGICALLY MODULATED, REPRESENTS A STRATEGY FOR THE PREVENTION AND TREATMENT OF ATHEROSCLEROSIS. THIS REVIEW FOCUSSES ON THE CURRENT UNDERSTANDING OF FACTORS CONTROLLING MACROPHAGE HETEROGENEITY AND FUNCTION IN ATHEROSCLEROSIS. PARTICULAR ATTENTION IS GIVEN TO THE MACROPHAGE INTRACELLULAR SIGNALING PATHWAYS AND TRANSCRIPTION FACTORS ACTIVATED BY BIOCHEMICAL AND BIOPHYSICAL STIMULI WITHIN PLAQUES, AND HOW THEY ARE INTEGRATED TO REGULATE PLAQUE FORMATION AND STABILITY. 2022 2 5423 32 REGULATION OF MACROPHAGE ACTIVATION AND DIFFERENTIATION IN ATHEROSCLEROSIS. CHRONIC INFLAMMATION IS A HALLMARK OF ATHEROSCLEROSIS AND MACROPHAGES PLAY A CENTRAL ROLE IN CONTROLLING INFLAMMATION AT ALL STAGES OF ATHEROSCLEROSIS. IN ATHEROSCLEROSIS, MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES ARE CONTINUOUSLY EXPOSED TO CHOLESTEROL, OXIDIZED LIPIDS, CELL DEBRIS, CYTOKINES, AND CHEMOKINES. NOT ONLY DO THESE STIMULI INDUCE A SPECIFIC MACROPHAGE PHENOTYPE, BUT THEY ALSO INTERACT EXTENSIVELY, LEADING TO MACROPHAGE HETEROGENEITY IN ATHEROSCLEROTIC PLAQUES. HEREIN, WE REVIEW THE DIVERSE PHENOTYPES OF MACROPHAGES, THE MECHANISMS UNDERLYING MACROPHAGE ACTIVATION, AND THE CONTRIBUTIONS OF MACROPHAGES TO ATHEROSCLEROSIS IN THIS CONTEXT. WE ALSO SUMMARIZE RECENT STUDIES ON FOAMY MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES IN PLAQUE DURING DISEASE PROGRESSION. WE PROVIDE A COMPREHENSIVE OVERVIEW OF TRANSCRIPTIONAL, EPIGENETIC, AND METABOLIC REPROGRAMMING OF MACROPHAGES AND DISCUSS THE EMERGING CONCEPTS OF TARGETING CYTOKINES AND MACROPHAGES TO MODULATE ATHEROSCLEROSIS. 2021 3 4097 28 MATRIX STIFFNESS REGULATES MACROPHAGE POLARIZATION IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE AND THE PATHOLOGICAL BASIS OF MANY FATAL CARDIOVASCULAR DISEASES. MACROPHAGES, THE MAIN INFLAMMATORY CELLS IN ATHEROSCLEROTIC PLAQUE, HAVE A PARADOX ROLE IN DISEASE PROGRESSION. IN RESPONSE TO DIFFERENT MICROENVIRONMENTS, MACROPHAGES MAINLY HAVE TWO POLARIZED DIRECTIONS: PRO-INFLAMMATORY MACROPHAGES AND ANTI-INFLAMMATORY MACROPHAGES. MORE AND MORE EVIDENCE SHOWS THAT MACROPHAGE IS MECHANOSENSITIVE AND MATRIX STIFFNESS REGULATE MACROPHAGE PHENOTYPES IN ATHEROSCLEROSIS. HOWEVER, THE MOLECULAR MECHANISM OF MATRIX STIFFNESS REGULATING MACROPHAGE POLARIZATION STILL LACKS IN-DEPTH RESEARCH, WHICH HINDERS THE DEVELOPMENT OF NEW ANTI-ATHEROSCLEROTIC THERAPIES. IN THIS REVIEW, WE DISCUSS THE IMPORTANT ROLE OF MATRIX STIFFNESS IN REGULATING MACROPHAGE POLARIZATION THROUGH MECHANICAL SIGNAL TRANSDUCTION (HIPPO, PIEZO, CYTOSKELETON, AND INTEGRIN) AND EPIGENETIC MECHANISMS (MIRNA, DNA METHYLATION, AND HISTONE). WE HOPE TO PROVIDE A NEW PERSPECTIVE FOR ATHEROSCLEROSIS THERAPY BY TARGETING MATRIX STIFFNESS AND MACROPHAGE POLARIZATION. 2022 4 4598 25 NATURAL PRODUCTS: THE ROLE AND MECHANISM IN LOW-DENSITY LIPOPROTEIN OXIDATION AND ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY, METABOLIC, AND EPIGENETIC DISEASE, WHICH LEADS TO THE LIFE-THREATENING CORONARY ARTERY DISEASE. EMERGING STUDIES FROM BENCH TO BEDSIDE HAVE DEMONSTRATED THE PIVOTAL ROLE OF LOW-DENSITY LIPOPROTEIN (LDL) OXIDATION IN THE INITIATION AND PROGRESSION OF ATHEROSCLEROSIS. THIS ARTICLE HEREBY REVIEWS OXIDATION MECHANISM OF LDL, AND THE PRO-ATHEROGENIC AND BIOMARKER ROLE OF OXIDIZED LDL IN ATHEROSCLEROSIS. WE ALSO REVIEW THE PHARMACOLOGICAL EFFECTS OF SEVERAL REPRESENTATIVE NATURAL PRODUCTS (VITAMIN E, RESVERATROL, QUERCETIN, PROBUCOL, TANSHINONE IIA, EPIGALLOCATECHIN GALLATE, AND LYCOPENE) IN PROTECTING AGAINST LDL OXIDATION AND ATHEROSCLEROSIS. CLINICAL AND BASIC RESEARCH SUPPORTS THE BENEFICIAL EFFECTS OF THESE NATURAL PRODUCTS IN INHIBITING LDL OXIDATION AND PREVENTING ATHEROSCLEROSIS, BUT THE DATA ARE STILL CONTROVERSIAL. THIS MAY BE RELATED TO FACTORS SUCH AS THE POPULATION AND THE DOSAGE AND TIME OF TAKING NATURAL PRODUCTS INVOLVED IN DIFFERENT STUDIES. UNDERSTANDING THE MECHANISM OF LDL OXIDATION AND EFFECT OF OXIDIZED LDL HELP RESEARCHERS TO FIND NOVEL THERAPIES AGAINST ATHEROSCLEROSIS. 2021 5 539 15 ATHEROSCLEROSIS IS AN EPIGENETIC DISEASE. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY AND LIPID-DEPOSITORY DISEASE THAT EVENTUALLY LEADS TO ACUTE CARDIOVASCULAR EVENTS. EMERGING EVIDENCE SUPPORTS THAT EPIGENETIC PROCESSES SUCH AS DNA METHYLATION, HISTONE MODIFICATION, AND NONCODING RNAS PLAY AN IMPORTANT ROLE IN PLAQUE PROGRESSION AND VULNERABILITY, HIGHLIGHTING THE THERAPEUTIC POTENTIAL OF EPIGENETIC DRUGS IN CARDIOVASCULAR THERAPEUTICS. 2018 6 4489 32 MONOCYTE AND MACROPHAGE IMMUNOMETABOLISM IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS CHARACTERIZED BY CHRONIC LOW GRADE INFLAMMATION OF ARTERIES THAT RESULTS IN THE DEVELOPMENT OF LIPID DENSE PLAQUES. CHRONIC INFLAMMATION INDUCED BY WESTERN-TYPE DIET IS ASSOCIATED WITH THE RISK OF DEVELOPING ATHEROSCLEROSIS, AND NEW INSIGHTS SHED LIGHT ON THE IMPORTANCE OF METABOLIC AND FUNCTIONAL REPROGRAMMING IN MONOCYTES AND MACROPHAGES FOR PROGRESSION OF ATHEROSCLEROSIS. THIS REVIEW AIMS TO PROVIDE AN OVERVIEW OF OUR CURRENT UNDERSTANDING INTO HOW THE METABOLIC REPROGRAMMING OF GLUCOSE, CHOLESTEROL, FATTY ACID, AND AMINO ACID METABOLISM IN MACROPHAGES CONTRIBUTES TO INFLAMMATION DURING ATHEROSCLEROSIS. RECENT INSIGHTS SUGGEST THAT TRANSCRIPTIONAL AND EPIGENETIC ADAPTATION WITHIN INNATE IMMUNE CELLS (TERMED TRAINED IMMUNITY) PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF ATHEROSCLEROSIS. WE PROPOSE THAT METABOLIC CHANGES INDUCED BY PRO-ATHEROGENIC LIPOPROTEINS PARTLY MEDIATE THESE CHANGES IN TRAINED MACROPHAGES. FINALLY, WE DISCUSS THE POSSIBILITY OF MANIPULATING CELLULAR METABOLISM OF IMMUNE CELLS FOR TARGETED THERAPEUTIC INTERVENTION AGAINST ATHEROSCLEROSIS. 2018 7 1712 44 DYSFUNCTIONAL VASCULAR ENDOTHELIUM AS A DRIVER OF ATHEROSCLEROSIS: EMERGING INSIGHTS INTO PATHOGENESIS AND TREATMENT. ATHEROSCLEROSIS, THE CHRONIC ACCUMULATION OF CHOLESTEROL-RICH PLAQUE WITHIN ARTERIES, IS ASSOCIATED WITH A BROAD SPECTRUM OF CARDIOVASCULAR DISEASES INCLUDING MYOCARDIAL INFARCTION, AORTIC ANEURYSM, PERIPHERAL VASCULAR DISEASE, AND STROKE. ATHEROSCLEROTIC CARDIOVASCULAR DISEASE REMAINS A LEADING CAUSE OF MORTALITY IN HIGH-INCOME COUNTRIES AND RECENT YEARS HAVE WITNESSED A NOTABLE INCREASE IN PREVALENCE WITHIN LOW- AND MIDDLE-INCOME REGIONS OF THE WORLD. CONSIDERING THIS PROMINENT AND EVOLVING GLOBAL BURDEN, THERE IS A NEED TO IDENTIFY THE CELLULAR MECHANISMS THAT UNDERLIE THE PATHOGENESIS OF ATHEROSCLEROSIS TO DISCOVER NOVEL THERAPEUTIC TARGETS FOR PREVENTING OR MITIGATING ITS CLINICAL SEQUELAE. DESPITE DECADES OF RESEARCH, WE STILL DO NOT FULLY UNDERSTAND THE COMPLEX CELL-CELL INTERACTIONS THAT DRIVE ATHEROSCLEROSIS, BUT NEW INVESTIGATIVE APPROACHES ARE RAPIDLY SHEDDING LIGHT ON THESE ESSENTIAL MECHANISMS. THE VASCULAR ENDOTHELIUM RESIDES AT THE INTERFACE OF SYSTEMIC CIRCULATION AND THE UNDERLYING VESSEL WALL AND PLAYS AN ESSENTIAL ROLE IN GOVERNING PATHOPHYSIOLOGICAL PROCESSES DURING ATHEROGENESIS. IN THIS REVIEW, WE PRESENT EMERGING EVIDENCE THAT IMPLICATES THE ACTIVATED ENDOTHELIUM AS A DRIVER OF ATHEROSCLEROSIS BY DIRECTING SITE-SPECIFICITY OF PLAQUE FORMATION AND BY PROMOTING PLAQUE DEVELOPMENT THROUGH INTRACELLULAR PROCESSES, WHICH REGULATE ENDOTHELIAL CELL PROLIFERATION AND TURNOVER, METABOLISM, PERMEABILITY, AND PLASTICITY. MOREOVER, WE HIGHLIGHT NOVEL MECHANISMS OF INTERCELLULAR COMMUNICATION BY WHICH ENDOTHELIAL CELLS MODULATE THE ACTIVITY OF KEY VASCULAR CELL POPULATIONS INVOLVED IN ATHEROGENESIS, AND DISCUSS HOW ENDOTHELIAL CELLS CONTRIBUTE TO RESOLUTION BIOLOGY - A PROCESS THAT IS DYSREGULATED IN ADVANCED PLAQUES. FINALLY, WE DESCRIBE IMPORTANT FUTURE DIRECTIONS FOR PRECLINICAL ATHEROSCLEROSIS RESEARCH, INCLUDING EPIGENETIC AND TARGETED THERAPIES, TO LIMIT THE PROGRESSION OF ATHEROSCLEROSIS IN AT-RISK OR AFFECTED PATIENTS. 2021 8 3776 35 INTERACTIONS BETWEEN DYSLIPIDEMIA AND THE IMMUNE SYSTEM AND THEIR RELEVANCE AS PUTATIVE THERAPEUTIC TARGETS IN ATHEROSCLEROSIS. CARDIOVASCULAR DISEASE (CVD) CONTINUES TO BE A LEADING CAUSE OF DEATH WORLDWIDE WITH ATHEROSCLEROSIS BEING THE MAJOR UNDERLYING PATHOLOGY. THE INTERPLAY BETWEEN LIPIDS AND IMMUNE CELLS IS BELIEVED TO BE A DRIVING FORCE IN THE CHRONIC INFLAMMATION OF THE ARTERIAL WALL DURING ATHEROGENESIS. ATHEROSCLEROSIS IS INITIATED AS LIPID PARTICLES ACCUMULATE AND BECOME TRAPPED IN VESSEL WALLS. THE SUBSEQUENT IMMUNE RESPONSE, INVOLVING BOTH ADAPTIVE AND IMMUNE CELLS, PROGRESSES PLAQUE DEVELOPMENT, WHICH MAY BE EXACERBATED UNDER DYSLIPIDEMIC CONDITIONS. BROAD EVIDENCE, ESPECIALLY FROM ANIMAL MODELS, CLEARLY DEMONSTRATES THE EFFECT OF LIPIDS ON IMMUNE CELLS FROM THEIR DEVELOPMENT IN THE BONE MARROW TO THEIR PHENOTYPIC SWITCHING IN CIRCULATION. INTERESTINGLY, RECENT RESEARCH HAS ALSO SHOWN A LONG-LASTING EPIGENETIC SIGNATURE FROM LIPIDS ON IMMUNE CELLS. TRADITIONALLY, CARDIOVASCULAR THERAPIES HAVE APPROACHED ATHEROSCLEROSIS THROUGH LIPID-LOWERING MEDICATIONS BECAUSE, UNTIL RECENTLY, ANTI-INFLAMMATORY THERAPIES HAVE BEEN LARGELY UNSUCCESSFUL IN CLINICAL TRIALS. HOWEVER, THE RECENT CANAKINUMAB ANTIINFLAMMATORY THROMBOSIS OUTCOMES STUDY (CANTOS) PROVIDED PIVOTAL SUPPORT OF THE INFLAMMATORY HYPOTHESIS OF ATHEROSCLEROSIS IN MAN SPURRING ON ANTI-INFLAMMATORY STRATEGIES TO TREAT ATHEROSCLEROSIS. IN THIS REVIEW, WE DESCRIBE THE INTERACTIONS BETWEEN LIPIDS AND IMMUNE CELLS ALONG WITH THEIR SPECIFIC OUTCOMES AS WELL AS DISCUSS THEIR FUTURE PERSPECTIVE AS POTENTIAL CARDIOVASCULAR TARGETS. 2019 9 5933 39 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 10 2378 34 EPIGENETIC REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING IN ATHEROSCLEROTIC ARTERY REMODELING: A MINI-REVIEW. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY EXTENSIVE REMODELING OF MEDIUM AND LARGE-SIZED ARTERIES. INWARD REMODELING (=LUMEN SHRINKAGE) OF THE VASCULAR WALLS IS THE UNDERLYING CAUSE FOR ISCHEMIA IN TARGET ORGANS. THEREFORE, INWARD REMODELING CAN BE CONSIDERED THE PREDOMINANT FEATURE OF ATHEROSCLEROTIC PATHOLOGY. OUTWARD REMODELING (=LUMEN ENLARGEMENT) IS A PHYSIOLOGICAL RESPONSE COMPENSATING FOR LUMEN SHRINKAGE CAUSED BY NEOINTIMAL HYPERPLASIA, BUT AS A PATHOLOGICAL RESPONSE TO CHANGES IN BLOOD FLOW, OUTWARD REMODELING LEADS TO SUBSTANTIAL ARTERIAL WALL THINNING. THINNED VASCULAR WALLS ARE PRONE TO RUPTURE, AND SUBSEQUENT THROMBUS FORMATION ACCOUNTS FOR THE MAJORITY OF ACUTE CARDIOVASCULAR EVENTS. PATHOLOGICAL REMODELING IS DRIVEN BY INFLAMMATORY CELLS WHICH INDUCE VASCULAR SMOOTH MUSCLE CELLS TO SWITCH FROM QUIESCENT TO A PROLIFERATIVE AND MIGRATORY PHENOTYPE. AFTER DECADES OF INTENSIVE RESEARCH, THE MOLECULAR MECHANISMS OF ARTERIAL REMODELING ARE STARTING TO UNFOLD. IN THIS MINI-REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING FROM THE CONTRACTILE TO THE SYNTHETIC PHENOTYPE INVOLVED IN ARTERIAL REMODELING AND DISCUSS POTENTIAL THERAPEUTIC OPTIONS. 2021 11 2291 26 EPIGENETIC REGULATION IN PATHOLOGY OF ATHEROSCLEROSIS: A NOVEL PERSPECTIVE. ATHEROSCLEROSIS, CHARACTERIZED BY ATHEROSCLEROTIC PLAQUES, IS A COMPLEX PATHOLOGICAL PROCESS THAT INVOLVES DIFFERENT CELL TYPES AND CAN BE SEEN AS A CHRONIC INFLAMMATORY DISEASE. IN THE ADVANCED STAGE, THE RUPTURED ATHEROSCLEROTIC PLAQUE CAN INDUCE DEADLY ACCIDENTS INCLUDING ISCHEMIC STROKE AND MYOCARDIAL INFARCTION. EPIGENETICS REGULATION, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA MODIFICATION. MAINTAINS CELLULAR IDENTITY VIA AFFECTING THE CELLULAR TRANSCRIPTOME. THE EPIGENETIC MODIFICATION PROCESS, MEDIATING BY EPIGENETIC ENZYMES, IS DYNAMIC UNDER VARIOUS STIMULI, WHICH CAN BE REVERSELY ALTERED. RECENTLY, NUMEROUS STUDIES HAVE EVIDENCED THE CLOSE RELATIONSHIP BETWEEN ATHEROSCLEROSIS AND EPIGENETIC REGULATIONS IN ATHEROSCLEROSIS, PROVIDING US WITH A NOVEL PERSPECTIVE IN RESEARCHING MECHANISMS AND FINDING NOVEL THERAPEUTIC TARGETS OF THIS SERIOUS DISEASE. HERE, WE CRITICALLY REVIEW THE RECENT DISCOVERIES BETWEEN EPIGENETIC REGULATION MECHANISMS IN ATHEROSCLEROSIS. 2021 12 3734 38 INNATE IMMUNE MEMORY IN MONOCYTES AND MACROPHAGES: THE POTENTIAL THERAPEUTIC STRATEGIES FOR ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A COMPLEX METABOLIC DISEASE CHARACTERIZED BY THE DYSFUNCTION OF LIPID METABOLISM AND CHRONIC INFLAMMATION IN THE INTIMAL SPACE OF THE VESSEL. AS THE MOST ABUNDANT INNATE IMMUNE CELLS, MONOCYTE-DERIVED MACROPHAGES PLAY A PIVOTAL ROLE IN THE INFLAMMATORY RESPONSE, CHOLESTEROL METABOLISM, AND FOAM CELL FORMATION. IN RECENT DECADES, IT HAS BEEN DEMONSTRATED THAT MONOCYTES AND MACROPHAGES CAN ESTABLISH INNATE IMMUNE MEMORY (ALSO TERMED TRAINED IMMUNITY) VIA ENDOGENOUS AND EXOGENOUS ATHEROGENIC STIMULI AND EXHIBIT A LONG-LASTING PROINFLAMMATORY PHENOTYPE. THE IMPORTANT CELLULAR METABOLISM PROCESSES, INCLUDING GLYCOLYSIS, OXIDATIVE PHOSPHORYLATION (OXPHOS), THE TRICARBOXYLIC ACID (TCA) CYCLE, FATTY ACID SYNTHESIS, AND CHOLESTEROL SYNTHESIS, ARE REPROGRAMMED. TRAINED MONOCYTES/MACROPHAGES WITH INNATE IMMUNE MEMORY CAN BE PERSISTENTLY HYPERACTIVATED AND CAN UNDERGO EXTENSIVE EPIGENETIC REWIRING, WHICH CONTRIBUTES TO THE PATHOPHYSIOLOGICAL DEVELOPMENT OF ATHEROSCLEROSIS VIA INCREASED PROINFLAMMATORY CYTOKINE PRODUCTION AND LIPID ACCUMULATION. HERE, WE PROVIDE AN OVERVIEW OF THE REGULATION OF CELLULAR METABOLIC PROCESSES AND EPIGENETIC MODIFICATIONS OF INNATE IMMUNE MEMORY IN MONOCYTES/MACROPHAGES AS WELL AS THE POTENTIAL ENDOGENOUS AND EXOGENOUS STIMULATIONS INVOLVED IN THE PROGRESSION OF ATHEROSCLEROSIS THAT HAVE BEEN REPORTED RECENTLY. THESE ELUCIDATIONS MIGHT BE BENEFICIAL FOR FURTHER UNDERSTANDING INNATE IMMUNE MEMORY AND THE DEVELOPMENT OF THERAPEUTIC STRATEGIES FOR INFLAMMATORY DISEASES AND ATHEROSCLEROSIS. 2022 13 6498 32 TRAINED IMMUNITY IN MONOCYTE/MACROPHAGE: NOVEL MECHANISM OF PHYTOCHEMICALS IN THE TREATMENT OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. ATHEROSCLEROSIS (AS) IS THE PATHOLOGY OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASES (ASCVD), CHARACTERIZED BY PERSISTENT CHRONIC INFLAMMATION IN THE VESSEL WALL, IN WHICH MONOCYTES/MACROPHAGES PLAY A KEY ROLE. IT HAS BEEN REPORTED THAT INNATE IMMUNE SYSTEM CELLS CAN ASSUME A PERSISTENT PROINFLAMMATORY STATE AFTER SHORT STIMULATION WITH ENDOGENOUS ATHEROGENIC STIMULI. THE PATHOGENESIS OF AS CAN BE INFLUENCED BY THIS PERSISTENT HYPERACTIVATION OF THE INNATE IMMUNE SYSTEM, WHICH IS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY HAS ALSO BEEN IMPLICATED AS A KEY PATHOLOGICAL MECHANISM, LEADING TO PERSISTENT CHRONIC INFLAMMATION IN AS. TRAINED IMMUNITY IS MEDIATED VIA EPIGENETIC AND METABOLIC REPROGRAMMING AND OCCURS IN MATURE INNATE IMMUNE CELLS AND THEIR BONE MARROW PROGENITORS. NATURAL PRODUCTS ARE PROMISING CANDIDATES FOR NOVEL PHARMACOLOGICAL AGENTS THAT CAN BE USED TO PREVENT OR TREAT CARDIOVASCULAR DISEASES (CVD). A VARIETY OF NATURAL PRODUCTS AND AGENTS EXHIBITING ANTIATHEROSCLEROTIC ABILITIES HAVE BEEN REPORTED TO POTENTIALLY INTERFERE WITH THE PHARMACOLOGICAL TARGETS OF TRAINED IMMUNITY. THIS REVIEW DESCRIBES IN AS MUCH DETAIL AS POSSIBLE THE MECHANISMS INVOLVED IN TRAINED IMMUNITY AND HOW PHYTOCHEMICALS OF THIS PROCESS INHIBIT AS BY AFFECTING TRAINED MONOCYTES/MACROPHAGES. 2023 14 3344 24 HISTONE DEACETYLASES (HDACS) AND ATHEROSCLEROSIS: A MECHANISTIC AND PHARMACOLOGICAL REVIEW. ATHEROSCLEROSIS (AS), THE MOST COMMON UNDERLYING PATHOLOGY FOR CORONARY ARTERY DISEASE, IS A CHRONIC INFLAMMATORY, PROLIFERATIVE DISEASE IN LARGE- AND MEDIUM-SIZED ARTERIES. THE VASCULAR ENDOTHELIUM IS IMPORTANT FOR MAINTAINING VASCULAR HEALTH. ENDOTHELIAL DYSFUNCTION IS A CRITICAL EARLY EVENT LEADING TO AS, WHICH IS A MAJOR RISK FACTOR FOR STROKE AND MYOCARDIAL INFARCTION. ACCUMULATING EVIDENCE HAS SUGGESTED THE CRITICAL ROLES OF HISTONE DEACETYLASES (HDACS) IN REGULATING VASCULAR CELL HOMEOSTASIS AND AS. THE PURPOSE OF THIS REVIEW IS TO PRESENT AN UPDATED VIEW ON THE ROLES OF HDACS (CLASS I, CLASS II, CLASS IV) AND HDAC INHIBITORS IN VASCULAR DYSFUNCTION AND AS. WE ALSO ELABORATE ON THE NOVEL THERAPEUTIC TARGETS AND AGENTS IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASES. 2020 15 2276 26 EPIGENETIC REGULATION AS A PROMISING TOOL FOR TREATMENT OF ATHEROSCLEROSIS. ATHEROSCLEROSIS IS ONE OF THE LEADING CAUSES OF DEATH FROM CARDIOVASCULAR DISEASE (CVD) THAT PRIMARILY INVOLVES MID SIZE AND LARGE ARTERIES. ATHEROSCLEROSIS IS ASSOCIATED WITH DISRUPTION OF LIPID METABOLISM AND CHRONIC INFLAMMATORY PROCESSES. ONE APPROACH FOR TREATMENT OF ATHEROSCLEROSIS IS BY VIRTUE OF EPIGENETIC CONTROL BY NONCODING RNAS (NCRNA) INCLUDING MIRNA, SIRNA AND LNCRNA, COMMONLY EMPLOYING MIRNA ANTAGONISTS AND MIMIC COMPOUNDS. HERE, WE REVIEW SUCH USAGES AS WELL AS OTHER APPROACHES FOR CORRECTING THE MOLECULAR LESIONS OF ATHEROSCLEROSIS INCLUDING SPECIFIC ACTIVATION OF ATHEROPROTECTIVE MIRNAS, AS WELL AS USE OF SIRNAS AND LCRNA TO CONTROL ABERRANT LIPID METABOLISM. WE ALSO DISCUSS SOME OF THESE TECHNOLOGIES THAT HAVE ALREADY SHOWN TO BE EFFECTIVE IN CLINICAL TRIALS AND ARE LIKELY TO ENTER THE CLINICAL ARENA. 2020 16 6497 36 TRAINED IMMUNITY IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. TRAINED IMMUNITY, ALSO KNOWN AS INNATE IMMUNE MEMORY, IS A PERSISTENT HYPER-RESPONSIVE FUNCTIONAL STATE OF INNATE IMMUNE CELLS. ACCUMULATING EVIDENCE IMPLICATES TRAINED IMMUNITY AS AN UNDERLYING MECHANISM OF CHRONIC INFLAMMATION IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. IN THIS CONTEXT, TRAINED IMMUNITY IS INDUCED BY ENDOGENOUS ATHEROSCLEROSIS-PROMOTING FACTORS, SUCH AS MODIFIED LIPOPROTEINS OR HYPERGLYCAEMIA, CAUSING BROAD METABOLIC AND EPIGENETIC REPROGRAMMING OF THE MYELOID CELL COMPARTMENT. IN ADDITION TO TRADITIONAL CARDIOVASCULAR RISK FACTORS, LIFESTYLE FACTORS, INCLUDING UNHEALTHY DIETS, SEDENTARY LIFESTYLE, SLEEP DEPRIVATION AND PSYCHOSOCIAL STRESS, AS WELL AS INFLAMMATORY COMORBIDITIES, HAVE BEEN SHOWN TO ACTIVATE TRAINED IMMUNITY-LIKE MECHANISMS IN BONE MARROW HAEMATOPOIETIC STEM CELLS. IN THIS REVIEW, WE DISCUSS THE MOLECULAR AND CELLULAR MECHANISMS OF TRAINED IMMUNITY, ITS SYSTEMIC REGULATION THROUGH HAEMATOPOIETIC PROGENITOR CELLS IN THE BONE MARROW, AND THE ACTIVATION OF THESE MECHANISMS BY CARDIOVASCULAR DISEASE RISK FACTORS. WE ALSO HIGHLIGHT OTHER TRAINED IMMUNITY FEATURES THAT ARE RELEVANT FOR ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, INCLUDING THE DIVERSE CELL TYPES THAT SHOW MEMORY CHARACTERISTICS AND TRANSGENERATIONAL INHERITANCE OF TRAINED IMMUNITY TRAITS. FINALLY, WE PROPOSE POTENTIAL STRATEGIES FOR THE THERAPEUTIC MODULATION OF TRAINED IMMUNITY TO MANAGE ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. 2023 17 2343 31 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 18 2289 26 EPIGENETIC REGULATION IN MONOCYTE/MACROPHAGE: A KEY PLAYER DURING ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE. RECENTLY, A GROWING BODY OF EVIDENCE EMPHASIZES THAT THE MONOCYTE AND MACROPHAGE DIFFERENTIATION AND ACTIVATION ARE KEY PROCESSES IN THE DEVELOPMENT OF ATHEROSCLEROSIS. HOWEVER, THE REGULATORY MECHANISM THAT MANIPULATES THE FUNCTION OF MONOCYTE AND MACROPHAGE IS STILL UNCLEAR. RECENT YEARS, EPIGENETIC MECHANISMS HAVE RECEIVED A WIDE ATTENTION AND BRING US A NEW FIELD OF VISION. MORE AND MORE EVIDENCE SHOWS THAT EPIGENETICS WEIGHS HEAVILY IN ATHEROSCLEROSIS BY REGULATING THE FUNCTION AND DIFFERENTIATION STATES OF MONOCYTE AND MACROPHAGE. IN THIS REVIEW, WE ILLUMINATE THE EPIGENETIC REGULATION MECHANISMS IN MONOCYTE AND MACROPHAGE AND THEIR CONTRIBUTIONS TO INFLAMMATORY PROCESSES OF ATHEROSCLEROSIS TO PROVIDE NEW THOUGHTS AND FIND NOVEL TARGETS OR BIOMARKERS FOR ATHEROSCLEROSIS. 2017 19 4585 31 NAD(+) AND VASCULAR DYSFUNCTION: FROM MECHANISMS TO THERAPEUTIC OPPORTUNITIES. NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)) IS AN ESSENTIAL AND PLEIOTROPIC COENZYME INVOLVED NOT ONLY IN CELLULAR ENERGY METABOLISM, BUT ALSO IN CELL SIGNALING, EPIGENETIC REGULATION, AND POST-TRANSLATIONAL PROTEIN MODIFICATIONS. VASCULAR DISEASE RISK FACTORS ARE ASSOCIATED WITH ABERRANT NAD(+) METABOLISM. CONVERSELY, THE THERAPEUTIC INCREASE OF NAD(+) LEVELS THROUGH THE ADMINISTRATION OF NAD(+) PRECURSORS OR INHIBITORS OF NAD(+)-CONSUMING ENZYMES REDUCES CHRONIC LOW-GRADE INFLAMMATION, REACTIVATES AUTOPHAGY AND MITOCHONDRIAL BIOGENESIS, AND ENHANCES OXIDATIVE METABOLISM IN VASCULAR CELLS OF HUMANS AND RODENTS WITH VASCULAR PATHOLOGIES. AS SUCH, NAD(+) HAS EMERGED AS A POTENTIAL TARGET FOR COMBATTING AGE-RELATED CARDIOVASCULAR AND CEREBROVASCULAR DISORDERS. THIS REVIEW DISCUSSES NAD(+)-REGULATED MECHANISMS CRITICAL FOR VASCULAR HEALTH AND SUMMARIZES NEW ADVANCES IN NAD(+) RESEARCH DIRECTLY RELATED TO VASCULAR AGING AND DISEASE, INCLUDING HYPERTENSION, ATHEROSCLEROSIS, CORONARY ARTERY DISEASE, AND AORTIC ANEURYSMS. FINALLY, WE ENUMERATE CHALLENGES AND OPPORTUNITIES FOR NAD(+) REPLETION THERAPY WHILE ANTICIPATING THE FUTURE OF THIS EXCITING RESEARCH FIELD, WHICH WILL HAVE A MAJOR IMPACT ON VASCULAR MEDICINE. 2022 20 5409 40 REGULATION OF ACETYLATION STATES BY NUTRIENTS IN THE INHIBITION OF VASCULAR INFLAMMATION AND ATHEROSCLEROSIS. ATHEROSCLEROSIS (AS) IS A CHRONIC METABOLIC DISORDER AND PRIMARY CAUSE OF CARDIOVASCULAR DISEASES, RESULTING IN SUBSTANTIAL MORBIDITY AND MORTALITY WORLDWIDE. INITIATED BY ENDOTHELIAL CELL STIMULATION, AS IS CHARACTERIZED BY ARTERIAL INFLAMMATION, LIPID DEPOSITION, FOAM CELL FORMATION, AND PLAQUE DEVELOPMENT. NUTRIENTS SUCH AS CAROTENOIDS, POLYPHENOLS, AND VITAMINS CAN PREVENT THE ATHEROSCLEROTIC PROCESS BY MODULATING INFLAMMATION AND METABOLIC DISORDERS THROUGH THE REGULATION OF GENE ACETYLATION STATES MEDIATED WITH HISTONE DEACETYLASES (HDACS). NUTRIENTS CAN REGULATE AS-RELATED EPIGENETIC STATES VIA SIRTUINS (SIRTS) ACTIVATION, SPECIFICALLY SIRT1 AND SIRT3. NUTRIENT-DRIVEN ALTERATIONS IN THE REDOX STATE AND GENE MODULATION IN AS PROGRESSION ARE LINKED TO THEIR PROTEIN DEACETYLATING, ANTI-INFLAMMATORY, AND ANTIOXIDANT PROPERTIES. NUTRIENTS CAN ALSO INHIBIT ADVANCED OXIDATION PROTEIN PRODUCT FORMATION, REDUCING ARTERIAL INTIMA-MEDIA THICKNESS EPIGENETICALLY. NONETHELESS, KNOWLEDGE GAPS REMAIN WHEN IT COMES TO UNDERSTANDING EFFECTIVE AS PREVENTION THROUGH EPIGENETIC REGULATION BY NUTRIENTS. THIS WORK REVIEWS AND CONFIRMS THE UNDERLYING MECHANISMS BY WHICH NUTRIENTS PREVENT ARTERIAL INFLAMMATION AND AS, FOCUSING ON THE EPIGENETIC PATHWAYS THAT MODIFY HISTONES AND NON-HISTONE PROTEINS BY REGULATING REDOX AND ACETYLATION STATES THROUGH HDACS SUCH AS SIRTS. THESE FINDINGS MAY SERVE AS A FOUNDATION FOR DEVELOPING POTENTIAL THERAPEUTIC AGENTS TO PREVENT AS AND CARDIOVASCULAR DISEASES BY EMPLOYING NUTRIENTS BASED ON EPIGENETIC REGULATION. 2023