1 6774 139 [AGE-RELATED VASCULAR CHANGES EXEMPLIFIED BY THE CAROTID ARTERY]. ONE OF THE MAIN RISK FACTORS FOR THE PRESENCE OF CAROTID STENOSIS AND CAROTID-RELATED STROKE IS AGE. THE AIM OF THIS REVIEW ARTICLE IS TO PRESENT THE CURRENT STATE OF KNOWLEDGE ON AGE-RELATED VASCULAR CHANGES USING CAROTID STENOSIS AS AN EXAMPLE.VASCULAR AGING (VASCULAR SENESCENCE) IS A DECREASE OF STRUCTURAL AND FUNCTIONAL PROPERTIES OF THE VESSEL WALL THAT TAKES PLACE ON DIFFERENT LEVELS. AT THE MULTICELLULAR LEVEL AN INCREASE IN VESSEL VOLUME AND DIAMETER AS WELL AS INTIMA MEDIA THICKNESS OCCURS WITH AGE MAINLY DUE TO ATHEROSCLEROTIC CHANGES IN THE VESSEL WALL. AT THE CELLULAR AND EXTRACELLULAR LEVELS THERE IS A DECREASE IN ELASTIN FIBERS, SMOOTH MUSCLE CELLS, AND TOTAL CELLULARITY, AN INCREASE IN LIPID, CHOLESTEROL, AND CALCIUM PHOSPHATE DEPOSITION AS WELL AS NEOVASCULARIZATION. THE CAUSES OF VASCULAR AGING AT THE MOLECULAR LEVEL INCLUDE, IN PARTICULAR OXIDATIVE STRESS, CHRONIC INFLAMMATORY RESPONSE, MITOCHONDRIAL DYSFUNCTION, EPIGENETIC CHANGES, DYSREGULATION OF THE EXPRESSION OF NON-CODING RNAS (NCRNAS), AND THE INCREASE IN SENESCENCE. AGE-RELATED LOSS OF TISSUE HEALING AND REPAIR CAPACITY MAKE PLAQUES MORE VULNERABLE AND, IN THE CASE OF THE CAROTID ARTERY, MORE SUSCEPTIBLE TO ISCHEMIC STROKE.INCREASING KNOWLEDGE OF THE INFLUENCE OF AGING ON THE EPIGENETICS AND NCRNAS IN ATHEROSCLEROTIC PLAQUES CAN IN THE FUTURE MORE ACCURATELY QUANTIFY INDIVIDUAL PATIENT RISK AND CONTRIBUTE TO THE DEVELOPMENT OF TARGETED THERAPEUTIC STRATEGIES; HOWEVER, FURTHER STUDIES ARE NEEDED IN THIS FIELD TO UNDERSTAND THE FULL EXTENT OF VASCULAR AGING AND ITS ASSOCIATED DISEASES SO THAT THESE CAN THEN BE SPECIFICALLY TARGETED. 2022 2 716 35 CALCIFIC AORTIC VALVE DISEASE-NATURAL HISTORY AND FUTURE THERAPEUTIC STRATEGIES. CALCIFIC AORTIC VALVE DISEASE (CAVD) IS THE MOST FREQUENT HEART VALVE DISORDER. IT IS CHARACTERIZED BY AN ACTIVE REMODELING PROCESS ACCOMPANIED WITH VALVE MINERALIZATION, THAT RESULTS IN A PROGRESSIVE AORTIC VALVE NARROWING, SIGNIFICANT RESTRICTION OF THE VALVULAR AREA, AND IMPAIRMENT OF BLOOD FLOW.THE PATHOPHYSIOLOGY OF CAVD IS A MULTIFACETED PROCESS, INVOLVING GENETIC FACTORS, CHRONIC INFLAMMATION, LIPID DEPOSITION, AND VALVE MINERALIZATION. MINERALIZATION IS STRICTLY RELATED TO THE INFLAMMATORY PROCESS IN WHICH BOTH, INNATE, AND ADAPTIVE IMMUNITY ARE INVOLVED. THE UNDERLYING PATHOPHYSIOLOGICAL PATHWAYS THAT GO FROM INFLAMMATION TO CALCIFICATION AND, FINALLY LEAD TO SEVERE STENOSIS, REMAIN, HOWEVER, INCOMPLETELY UNDERSTOOD. HISTOPATHOLOGICAL STUDIES ARE LIMITED TO PATIENTS WITH SEVERE CAVD AND NO SAMPLES ARE AVAILABLE FOR LONGITUDINAL STUDIES OF DISEASE PROGRESSION. THEREFORE, ALTERNATIVE ROUTES SHOULD BE EXPLORED TO INVESTIGATE THE PATHOGENESIS AND PROGRESSION OF CAVD.RECENTLY, INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC MARKERS SUCH AS NON-CODING RNAS ARE IMPLICATED IN THE LANDSCAPE OF PHENOTYPICAL CHANGES OCCURRING IN CAVD. FURTHERMORE, THE MICROBIOME, AN ESSENTIAL PLAYER IN SEVERAL DISEASES, INCLUDING THE CARDIOVASCULAR ONES, HAS RECENTLY BEEN LINKED TO THE INFLAMMATION PROCESS OCCURRING IN CAVD. IN THE PRESENT REVIEW, WE ANALYZE AND DISCUSS THE CAVD PATHOPHYSIOLOGY AND FUTURE THERAPEUTIC STRATEGIES, FOCUSING ON THE REAL AND PUTATIVE ROLE OF INFLAMMATION, CALCIFICATION, AND MICROBIOME. 2020 3 6516 35 TRANSCRIPTIONAL AND EPIGENETIC FACTORS ASSOCIATED WITH EARLY THROMBOSIS OF FEMORAL ARTERY INVOLVED IN ARTERIOVENOUS FISTULA. ARTERIOVENOUS FISTULAS (AVFS), CREATED FOR HEMODIALYSIS IN END-STAGE RENAL DISEASE PATIENTS, MATURE THROUGH THE OUTWARD REMODELING OF THE OUTFLOW VEIN. HOWEVER, EARLY THROMBOSIS AND CHRONIC INFLAMMATION ARE DETRIMENTAL TO THE PROCESS OF AVF MATURATION AND PRECIPITATE AVF MATURATION FAILURE. FOR THE SUCCESSFUL REMODELING OF THE OUTFLOW VEIN, BLOOD FLOW THROUGH THE FISTULA IS ESSENTIAL, BUT EARLY ARTERIAL THROMBOSIS ATTENUATES THIS BLOOD FLOW, AND THE VESSELS BECOME THROMBOSED AND STENOSED, LEADING TO AVF FAILURE. THE ALTERED EXPRESSION OF VARIOUS PROTEINS INVOLVED IN MAINTAINING VESSEL PATENCY OR THROMBOSIS IS REGULATED BY GENES OF WHICH THE EXPRESSION IS REGULATED BY TRANSCRIPTION FACTORS AND MICRORNAS. IN THIS STUDY, USING THROMBOSED AND STENOSED ARTERIES FOLLOWING AVF CREATION, WE DELINEATED TRANSCRIPTION FACTORS AND MICRORNAS ASSOCIATED WITH DIFFERENTIALLY EXPRESSED GENES IN BULK RNA SEQUENCING DATA USING UPSTREAM AND CAUSAL NETWORK ANALYSIS. WE OBSERVED CHANGES IN MANY TRANSCRIPTION FACTORS AND MICRORNAS THAT ARE INVOLVED IN ANGIOGENESIS; VASCULAR SMOOTH MUSCLE CELL PROLIFERATION, MIGRATION, AND PHENOTYPIC CHANGES; ENDOTHELIAL CELL FUNCTION; HYPOXIA; OXIDATIVE STRESS; VESSEL REMODELING; IMMUNE RESPONSES; AND INFLAMMATION. THESE FACTORS AND MICRORNAS PLAY A CRITICAL ROLE IN THE UNDERLYING MOLECULAR MECHANISMS IN AVF MATURATION. WE ALSO OBSERVED EPIGENETIC FACTORS INVOLVED IN GENE REGULATION ASSOCIATED WITH THESE MOLECULAR MECHANISMS. THE RESULTS OF THIS STUDY INDICATE THE IMPORTANCE OF INVESTIGATING THE TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF AVF MATURATION AND MATURATION FAILURE AND TARGETING FACTORS PRECIPITATING EARLY THROMBOSIS AND STENOSIS. 2022 4 1020 32 CIRCRNAS IN ATHEROSCLEROSIS, WITH SPECIAL EMPHASIS ON THE SPONGY EFFECT OF CIRCRNAS ON MIRNAS. ATHEROSCLEROSIS (AS) IS A CHRONIC INFLAMMATORY DISEASE, WHICH LEADS TO ATHEROSCLEROTIC RUPTURE, LUMEN STENOSIS AND THROMBOSIS, AND OFTEN ENDANGERS LIFE. CIRCULAR RNAS (CIRCRNAS) ARE A SPECIAL CLASS OF NON-CODING RNA MOLECULES, WHOSE ABNORMAL EXPRESSION HAS BEEN PROVED TO BE CLOSELY RELATED TO HUMAN DISEASES, INCLUDING AS. BOTH THE ABNORMAL REGULATION OF CIRCRNAS AND THE SPONGING EFFECT ON MIRNAS WOULD LEAD TO CHANGES IN GENE EXPRESSION IN THE FORM OF EPIGENETIC MODIFICATION, ULTIMATELY LEADING TO THE FORMATION OF AS. CIRCRNAS CAN BE USED AS PERIPHERAL BLOOD MARKERS OF AS, AND PLAY AN IMPORTANT REGULATORY ROLE IN THE PROLIFERATION, MIGRATION, INFLAMMATION AND APOPTOSIS OF VASCULAR SMOOTH MUSCLE CELLS, ENDOTHELIAL CELLS AND MACROPHAGE, WHICH ARE KEY CELLS FOR THE DEVELOPMENT OF AS. THE IN-DEPTH UNDERSTANDING OF CIRCRNAS IN AS NOT ONLY PROVIDES A NEW METHOD FOR THE DIAGNOSIS OF AS, BUT ALSO PROVIDES A NEW IDEA FOR THE TREATMENT OF AS. 2023 5 2378 31 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 6 2587 33 EPIGENETICS OF PARAOXONASES. PURPOSE OF REVIEW: STUDIES HAVE SHOWN THE THREE-MEMBER PARAOXONASE (PON) MULTIGENE FAMILY TO BE INVOLVED IN THE DEVELOPMENT OF A LARGE VARIETY OF DISEASES WITH AN INFLAMMATORY COMPONENT. ENVIRONMENTAL FACTORS SUCH AS LIFESTYLE-RELATED FACTORS DIFFER WIDELY BETWEEN POPULATIONS AND IT IS IMPORTANT TO CONSIDER THAT THEIR IMPACTS MAY BE EXERTED THROUGH THE EPIGENETIC MECHANISMS, WHICH CONNECT GENES, THE ENVIRONMENT AND DISEASE DEVELOPMENT AND ARE A POTENTIAL THERAPEUTIC AVENUE. RECENT FINDINGS: IN THE REVIEW PERIOD, VERY LITTLE WAS PUBLISHED ON EPIGENETICS OF PON2 OR PON3, MOSTLY ON THEIR DIAGNOSTIC VALUE IN CANCER BY MEASURING METHYLATION LEVELS OF THESE GENES. HOWEVER, THE PICTURE IS MORE PROMISING WITH PON1. HERE, SEVERAL STUDIES HAVE LINKED THE EPIGENETIC REGULATION OF PON1 TO VARIOUS METABOLIC PROCESSES AND PARTICULARLY TO THE DEVELOPMENT OF SEVERAL DISEASES, INCLUDING STROKE, HEART DISEASE, AORTIC VALVE STENOSIS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. SUMMARY: STUDIES INTO THE EPIGENETIC REGULATION OF THE PON FAMILY ARE IN THEIR INFANCY. HOWEVER, RECENT STUDIES LINKING EPIGENETIC REGULATION OF PON1 TO DISEASE DEVELOPMENT WILL ENCOURAGE FURTHER RESEARCH AND OPEN UP THE POSSIBILITY FOR NEW POTENTIAL THERAPEUTIC INTERVENTIONS. 2020 7 539 17 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 8 2314 26 EPIGENETIC REGULATION OF ENDOTHELIAL-TO-MESENCHYMAL TRANSITION IN CHRONIC HEART DISEASE. ENDOTHELIAL-TO-MESENCHYMAL TRANSITION (ENDMT) IS A PROCESS IN WHICH ENDOTHELIAL CELLS LOSE THEIR PROPERTIES AND TRANSFORM INTO FIBROBLAST-LIKE CELLS. THIS TRANSITION PROCESS CONTRIBUTES TO CARDIAC FIBROSIS, A COMMON FEATURE OF PATIENTS WITH CHRONIC HEART FAILURE. TO DATE, NO SPECIFIC THERAPIES TO HALT OR REVERSE CARDIAC FIBROSIS ARE AVAILABLE, SO KNOWLEDGE OF THE UNDERLYING MECHANISMS OF CARDIAC FIBROSIS IS URGENTLY NEEDED. IN ADDITION, ENDMT CONTRIBUTES TO OTHER CARDIOVASCULAR PATHOLOGIES SUCH AS ATHEROSCLEROSIS AND PULMONARY HYPERTENSION, BUT ALSO TO CANCER AND ORGAN FIBROSIS. REMARKABLY, THE MOLECULAR MECHANISMS DRIVING ENDMT ARE LARGELY UNKNOWN. EPIGENETICS PLAY AN IMPORTANT ROLE IN REGULATING GENE TRANSCRIPTION AND TRANSLATION AND HAVE BEEN IMPLICATED IN THE ENDMT PROCESS. THEREFORE, EPIGENETICS MIGHT BE THE MISSING LINK IN UNRAVELING THE UNDERLYING MECHANISMS OF ENDMT. HERE, WE REVIEW THE INVOLVEMENT OF EPIGENETIC REGULATORS DURING ENDMT IN THE CONTEXT OF CARDIAC FIBROSIS. THE ROLE OF DNA METHYLATION, HISTONE MODIFICATIONS (ACETYLATION AND METHYLATION), AND NONCODING RNAS (MICRORNAS, LONG NONCODING RNAS, AND CIRCULAR RNAS) IN THE FACILITATION AND INHIBITION OF ENDMT ARE DISCUSSED, AND POTENTIAL THERAPEUTIC EPIGENETIC TARGETS WILL BE HIGHLIGHTED. 2018 9 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 10 4467 36 MOLECULAR MECHANISMS OF VASCULAR HEALTH: INSIGHTS FROM VASCULAR AGING AND CALCIFICATION. CARDIOVASCULAR DISEASE IS THE MOST COMMON CAUSE OF DEATH WORLDWIDE, ESPECIALLY BEYOND THE AGE OF 65 YEARS, WITH THE VAST MAJORITY OF MORBIDITY AND MORTALITY DUE TO MYOCARDIAL INFARCTION AND STROKE. VASCULAR PATHOLOGY STEMS FROM A COMBINATION OF GENETIC RISK, ENVIRONMENTAL FACTORS, AND THE BIOLOGIC CHANGES ASSOCIATED WITH AGING. THE PATHOGENESIS UNDERLYING THE DEVELOPMENT OF VASCULAR AGING, AND VASCULAR CALCIFICATION WITH AGING, IN PARTICULAR, IS STILL NOT FULLY UNDERSTOOD. ACCUMULATING DATA SUGGESTS THAT GENETIC RISK, LIKELY COMPOUNDED BY EPIGENETIC MODIFICATIONS, ENVIRONMENTAL FACTORS, INCLUDING DIABETES AND CHRONIC KIDNEY DISEASE, AND THE PLASTICITY OF VASCULAR SMOOTH MUSCLE CELLS TO ACQUIRE AN OSTEOGENIC PHENOTYPE ARE MAJOR DETERMINANTS OF AGE-ASSOCIATED VASCULAR CALCIFICATION. UNDERSTANDING THE MOLECULAR MECHANISMS UNDERLYING GENETIC AND MODIFIABLE RISK FACTORS IN REGULATING AGE-ASSOCIATED VASCULAR PATHOLOGY MAY INSPIRE STRATEGIES TO PROMOTE HEALTHY VASCULAR AGING. THIS ARTICLE SUMMARIZES CURRENT KNOWLEDGE OF CONCEPTS AND MECHANISMS OF AGE-ASSOCIATED VASCULAR DISEASE, WITH AN EMPHASIS ON VASCULAR CALCIFICATION. 2023 11 5933 44 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 12 2223 33 EPIGENETIC MODIFICATIONS IN SPINAL LIGAMENT AGING. SPINAL STENOSIS IS A COMMON DEGENERATIVE SPINE DISORDER IN THE AGED POPULATION AND THE SPINAL LIGAMENT AGING IS A MAIN CONTRIBUTOR TO THIS CHRONIC DISEASE. HOWEVER, THE UNDERLYING MECHANISMS OF SPINAL LIGAMENT AGING REMAIN UNCLEAR. EPIGENETICS IS THE STUDY OF HERITABLE AND REVERSIBLE CHANGES IN THE FUNCTION OF A GENE OR GENOME THAT OCCUR WITHOUT ANY ALTERATION IN THE PRIMARY DNA SEQUENCE. EPIGENETIC ALTERATIONS HAVE BEEN DEMONSTRATED TO PLAY CRUCIAL ROLES IN AGE-RELATED DISEASES AND CONDITIONS, AND THEY ARE RECENTLY STUDIED AS BIOMARKERS AND THERAPEUTIC TARGETS IN THE FIELD OF CANCER RESEARCH. THE MAIN EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION ALTERATION, HISTONE MODIFICATIONS AS WELL AS DYSREGULATED NONCODING RNA MODULATION, HAVE ALL BEEN IMPLICATED IN SPINAL LIGAMENT AGING DISEASES. DNA METHYLATION MODULATES THE EXPRESSION OF CRITICAL GENES INCLUDING WNT5A, GDNF, ACSM5, MIR-497 AND MIR-195 DURING SPINAL LIGAMENT DEGENERATION. HISTONE MODIFICATIONS WIDELY AFFECT GENE EXPRESSION AND OBVIOUS HISTONE MODIFICATION ABNORMALITIES HAVE BEEN FOUND IN SPINAL LIGAMENT AGING. MICRORNAS (MIRNAS), LONG NONCODING RNAS (LNCRNAS) AND CIRCULAR RNAS (CIRCRNAS) EXERT CRUCIAL REGULATING EFFECTS ON SPINAL LIGAMENT AGING CONDITIONS VIA TARGETING VARIOUS OSTEOGENIC OR FIBROGENIC DIFFERENTIATION RELATED GENES. TO OUR KNOWLEDGE, THERE IS NO SYSTEMATIC REVIEW YET TO SUMMARIZE THE INVOLVEMENT OF EPIGENETIC MECHANISMS OF SPINAL LIGAMENT AGING IN DEGENERATIVE SPINAL DISEASES. IN THIS STUDY, WE SYSTEMATICALLY DISCUSSED THE DIFFERENT EPIGENETIC MODIFICATIONS AND THEIR POTENTIAL FUNCTIONS IN SPINAL LIGAMENT AGING PROCESS. 2022 13 1872 32 EMERGING ROLE OF LONG NON-CODING RNAS IN ENDOTHELIAL DYSFUNCTION AND THEIR MOLECULAR MECHANISMS. LONG NON-CODING RNAS (LNCRNAS) ARE THE NOVEL CLASS OF TRANSCRIPTS INVOLVED IN TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, TRANSLATIONAL, AND POST-TRANSLATIONAL REGULATION OF PHYSIOLOGY AND THE PATHOLOGY OF DISEASES. STUDIES HAVE EVIDENCED THAT THE IMPAIRMENT OF ENDOTHELIUM IS A CRITICAL EVENT IN THE PATHOGENESIS OF ATHEROSCLEROSIS AND ITS COMPLICATIONS. ENDOTHELIAL DYSFUNCTION IS CHARACTERIZED BY AN IMBALANCE IN VASODILATION AND VASOCONSTRICTION, OXIDATIVE STRESS, PROINFLAMMATORY FACTORS, AND NITRIC OXIDE BIOAVAILABILITY. DISRUPTION OF THE ENDOTHELIAL BARRIER PERMEABILITY, THE FIRST STEP IN DEVELOPING ATHEROSCLEROTIC LESIONS IS A CONSEQUENCE OF ENDOTHELIAL DYSFUNCTION. THOUGH SEVERAL FACTORS INTERFERE WITH THE NORMAL FUNCTIONING OF THE ENDOTHELIUM, INTRINSIC EPIGENETIC MECHANISMS GOVERNING ENDOTHELIAL FUNCTION ARE REGULATED BY LNCRNAS AND PERTURBATIONS CONTRIBUTE TO THE PATHOGENESIS OF THE DISEASE. THIS REVIEW COMPREHENSIVELY ADDRESSES THE BIOGENESIS OF LNCRNA AND MOLECULAR MECHANISMS UNDERLYING AND REGULATION IN ENDOTHELIAL FUNCTION. AN INSIGHT CORRELATING LNCRNAS AND ENDOTHELIAL DYSFUNCTION-ASSOCIATED DISEASES CAN POSITIVELY IMPACT THE DEVELOPMENT OF NOVEL BIOMARKERS AND THERAPEUTIC TARGETS IN ENDOTHELIAL DYSFUNCTION-ASSOCIATED DISEASES AND TREATMENT STRATEGIES. 2022 14 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 15 4191 36 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 16 4715 32 NON-CODING RNA REGULATION OF T CELL BIOLOGY: IMPLICATIONS FOR AGE-ASSOCIATED CARDIOVASCULAR DISEASES. PREVALENCE OF AGE-ASSOCIATED CARDIOVASCULAR DISEASES (CVD) HAS DRAMATICALLY INCREASED AS A RESULT OF IMPROVEMENTS IN LIFE EXPECTANCY. CHRONIC INFLAMMATION IS A SHARED PATHOPHYSIOLOGICAL FEATURE OF AGE-ASSOCIATED CVDS, INDICATING A ROLE FOR THE IMMUNE SYSTEM IN THE ONSET AND DEVELOPMENT OF CVDS. INDEED, AGEING ELICITS PROFOUND CHANGES IN BOTH THE CARDIOVASCULAR AND IMMUNE SYSTEM, ESPECIALLY IN THE T CELL COMPARTMENT. ALTHOUGH SUCH CHANGES HAVE BEEN WELL DESCRIBED AT THE CELLULAR LEVEL, THE MOLECULAR MECHANISMS UNDERLYING IMMUNE-MEDIATED CARDIOVASCULAR AGEING REMAIN LARGELY UNEXPLORED. NON-CODING RNAS (NCRNAS) COMPRISE A HETEROGENEOUS FAMILY OF RNA TRANSCRIPTS THAT REGULATE GENE EXPRESSION AT THE EPIGENETIC, TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND POST-TRANSLATIONAL LEVELS. NON-CODING RNAS HAVE RECENTLY EMERGED AS MASTER MODULATORS OF T CELL IMMUNITY. IN THIS REVIEW, THE STATE-OF-THE-ART KNOWLEDGE ON NCRNA REGULATORY EFFECTS OVER T CELL DIFFERENTIATION, FUNCTION, AND AGEING IN THE CONTEXT OF AGE-ASSOCIATED CVDS, SUCH AS ATHEROSCLEROSIS, ACUTE CORONARY SYNDROMES, AND HEART FAILURE, IS DISCUSSED. 2018 17 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 18 5264 29 PROMISING DIRECTIONS IN ATHEROSCLEROSIS TREATMENT BASED ON EPIGENETIC REGULATION USING MICRORNAS AND LONG NONCODING RNAS. ATHEROSCLEROSIS IS ONE OF THE LEADING CAUSES OF MORTALITY FROM CARDIOVASCULAR DISEASE (CVD) AND IS A CHRONIC INFLAMMATORY DISEASE OF THE MIDDLE AND LARGE ARTERIES CAUSED BY A DISRUPTION OF LIPID METABOLISM. NONCODING RNA (NCRNA), INCLUDING MICRORNA (MIRNA), SMALL INTERFERING RNA (SIRNA) AND LONG NONCODING RNA (LNCRNA), WAS INVESTIGATED FOR THE TREATMENT OF ATHEROSCLEROSIS. REGULATION OF THE EXPRESSION OF NONCODING RNA TARGETS THE CONSTITUENT ELEMENT OF THE PATHOGENESIS OF ATHEROSCLEROSIS. CURRENTLY, MIRNA THERAPY COMMONLY EMPLOYS MIRNA ANTAGONISTS AND MIMIC COMPOUNDS. IN THIS REVIEW, ATTENTION IS FOCUSED ON APPROACHES TO CORRECTING MOLECULAR DISORDERS BASED ON THE GENETIC REGULATION OF THE TRANSCRIPTION OF KEY GENES RESPONSIBLE FOR THE DEVELOPMENT OF ATHEROSCLEROSIS. PROMISING TECHNOLOGIES WERE CONSIDERED FOR THE TREATMENT OF ATHEROSCLEROSIS, AND EXAMPLES ARE GIVEN FOR TECHNOLOGIES THAT HAVE BEEN SHOWN TO BE EFFECTIVE IN CLINICAL TRIALS. 2019 19 4097 27 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 20 4120 37 MECHANISMS OF CARDIOVASCULAR DISORDERS IN PATIENTS WITH CHRONIC KIDNEY DISEASE: A PROCESS RELATED TO ACCELERATED SENESCENCE. CARDIOVASCULAR DISEASES (CVDS), ESPECIALLY THOSE INVOLVING A SYSTEMIC INFLAMMATORY PROCESS SUCH AS ATHEROSCLEROSIS, REMAIN THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD). CKD IS A SYSTEMIC CONDITION AFFECTING APPROXIMATELY 10% OF THE GENERAL POPULATION. THE PREVALENCE OF CKD HAS INCREASED OVER THE PAST DECADES BECAUSE OF THE AGING OF THE POPULATION WORLDWIDE. INDEED, CVDS IN PATIENTS WITH CKD CONSTITUTE A PREMATURE FORM OF CVD OBSERVED IN THE GENERAL POPULATION. MULTIPLE STUDIES INDICATE THAT PATIENTS WITH RENAL DISEASE UNDERGO ACCELERATED AGING, WHICH PRECIPITATES THE APPEARANCE OF PATHOLOGIES, INCLUDING CVDS, USUALLY ASSOCIATED WITH ADVANCED AGE. IN THIS REVIEW, WE DISCUSS SEVERAL ASPECTS THAT CHARACTERIZE CKD-ASSOCIATED CVDS, SUCH AS ETIOPATHOGENIC ELEMENTS THAT CKD PATIENTS SHARE WITH THE GENERAL POPULATION, CHANGES IN THE CELLULAR BALANCE OF REACTIVE OXYGEN SPECIES (ROS), AND THE ASSOCIATED PROCESS OF CELLULAR SENESCENCE. UREMIA-ASSOCIATED AGING IS LINKED WITH NUMEROUS CHANGES AT THE CELLULAR AND MOLECULAR LEVEL. THESE CHANGES ARE SIMILAR TO THOSE OBSERVED IN THE NORMAL PROCESS OF PHYSIOLOGIC AGING. WE ALSO DISCUSS NEW PERSPECTIVES IN THE STUDY OF CKD-ASSOCIATED CVDS AND EPIGENETIC ALTERATIONS IN INTERCELLULAR SIGNALING, MEDIATED BY MICRORNAS AND/OR EXTRACELLULAR VESICLES (EVS), WHICH PROMOTE VASCULAR DAMAGE AND SUBSEQUENT DEVELOPMENT OF CVD. UNDERSTANDING THE PROCESSES AND FACTORS INVOLVED IN ACCELERATED SENESCENCE AND OTHER ABNORMAL INTERCELLULAR SIGNALING WILL IDENTIFY NEW THERAPEUTIC TARGETS AND LEAD TO IMPROVED METHODS OF DIAGNOSIS AND MONITORING FOR PATIENTS WITH CKD-ASSOCIATED CVDS. 2020