1 444 143 AORTIC AND CAROTID ARTERIAL STIFFNESS AND EPIGENETIC REGULATOR GENE EXPRESSION CHANGES PRECEDE BLOOD PRESSURE RISE IN STROKE-PRONE DAHL SALT-SENSITIVE HYPERTENSIVE RATS. MULTIPLE CLINICAL STUDIES SHOW THAT ARTERIAL STIFFNESS, MEASURED AS PULSE WAVE VELOCITY (PWV), PRECEDES HYPERTENSION AND IS AN INDEPENDENT PREDICTOR OF HYPERTENSION END ORGAN DISEASES INCLUDING STROKE, CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASE. RISK FACTOR STUDIES FOR ARTERIAL STIFFNESS IMPLICATE AGE, HYPERTENSION AND SODIUM. HOWEVER, CAUSAL MECHANISMS LINKING RISK FACTOR TO ARTERIAL STIFFNESS REMAIN TO BE ELUCIDATED. HERE, WE STUDIED THE CAUSAL RELATIONSHIP OF ARTERIAL STIFFNESS AND HYPERTENSION IN THE NA-INDUCED, STROKE-PRONE DAHL SALT-SENSITIVE (S) HYPERTENSIVE RAT MODEL, AND ANALYZED PUTATIVE MOLECULAR MECHANISMS. STROKE-PRONE AND NON-STROKE-PRONE MALE AND FEMALE RATS WERE STUDIED AT 3- AND 6-WEEKS OF AGE FOR ARTERIAL STIFFNESS (PWV, STRAIN), BLOOD PRESSURE, VESSEL WALL HISTOLOGY, AND GENE EXPRESSION CHANGES. STUDIES SHOWED THAT INCREASED LEFT CAROTID AND AORTIC ARTERIAL STIFFNESS PRECEDED HYPERTENSION, PULSE PRESSURE WIDENING, AND STRUCTURAL WALL CHANGES AT THE 6-WEEK TIME-POINT. INSTEAD, DIFFERENTIAL GENE INDUCTION WAS DETECTED IMPLICATING MOLECULAR-FUNCTIONAL CHANGES IN EXTRACELLULAR MATRIX (ECM) STRUCTURAL CONSTITUENTS, MODIFIERS, CELL ADHESION, AND MATRICELLULAR PROTEINS, AS WELL AS IN ENDOTHELIAL FUNCTION, APOPTOSIS BALANCE, AND EPIGENETIC REGULATORS. IMMUNOSTAINING TESTING HISTONE MODIFIERS EP300, HDAC3, AND PRMT5 LEVELS CONFIRMED CAROTID ARTERY-UPREGULATION IN ALL THREE LAYERS: ENDOTHELIAL, SMOOTH MUSCLE AND ADVENTITIAL CELLS. OUR STUDY RECAPITULATES OBSERVATIONS IN HUMANS THAT GIVEN SALT-SENSITIVITY, INCREASED NA-INTAKE INDUCED ARTERIAL STIFFNESS BEFORE HYPERTENSION, INCREASED PULSE PRESSURE, AND STRUCTURAL VESSEL WALL CHANGES. DIFFERENTIAL GENE EXPRESSION CHANGES ASSOCIATED WITH ARTERIAL STIFFNESS SUGGEST A MOLECULAR MECHANISM LINKING SODIUM TO FULL-VESSEL WALL RESPONSE AFFECTING GENE-NETWORKS INVOLVED IN VASCULAR ECM STRUCTURE-FUNCTION, APOPTOSIS BALANCE, AND EPIGENETIC REGULATION. 2014 2 4097 25 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 3 172 36 ABSENCE OF HDAC3 BY MATRIX STIFFNESS PROMOTES CHROMATIN REMODELING AND FIBROBLAST ACTIVATION IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND FATAL DISEASE CHARACTERIZED BY PROGRESSIVE AND IRREVERSIBLE LUNG SCARRING ASSOCIATED WITH PERSISTENT ACTIVATION OF FIBROBLASTS. EPIGENETICS COULD INTEGRATE DIVERSE MICROENVIRONMENTAL SIGNALS, SUCH AS STIFFNESS, TO DIRECT PERSISTENT FIBROBLAST ACTIVATION. HISTONE MODIFICATIONS BY DEACETYLASES (HDAC) MAY PLAY AN ESSENTIAL ROLE IN THE GENE EXPRESSION CHANGES INVOLVED IN THE PATHOLOGICAL REMODELING OF THE LUNG. PARTICULARLY, HDAC3 IS CRUCIAL FOR MAINTAINING CHROMATIN AND REGULATING GENE EXPRESSION, BUT LITTLE IS KNOWN ABOUT ITS ROLE IN IPF. IN THE STUDY, CONTROL AND IPF-DERIVED FIBROBLASTS WERE USED TO DETERMINE THE INFLUENCE OF HDAC3 ON CHROMATIN REMODELING AND GENE EXPRESSION ASSOCIATED WITH IPF SIGNATURE. ADDITIONALLY, THE CELLS WERE GROWN ON HYDROGELS TO MIMIC THE STIFFNESS OF A FIBROTIC LUNG. OUR RESULTS SHOWED A DECREASED HDAC3 IN THE NUCLEUS OF IPF FIBROBLASTS, WHICH CORRELATES WITH CHANGES IN NUCLEUS SIZE AND HETEROCHROMATIN LOSS. THE INHIBITION OF HDAC3 WITH A PHARMACOLOGICAL INHIBITOR CAUSES HYPERACETYLATION OF H3K9 AND PROVOKES AN INCREASED EXPRESSION OF COL1A1, ACTA2, AND P21. COMPARABLE RESULTS WERE FOUND IN HYDROGELS, WHERE MATRIX STIFFNESS PROMOTES THE LOSS OF NUCLEAR HDAC3 AND INCREASES THE PROFIBROTIC SIGNATURE. FINALLY, LATRUNCULIN B WAS USED TO CONFIRM THAT CHANGES BY STIFFNESS DEPEND ON THE MECHANOTRANSDUCTION SIGNALS. TOGETHER, THESE RESULTS SUGGEST THAT HDAC3 COULD BE A LINK BETWEEN EPIGENETIC MECHANISMS AND THE FIBROTIC MICROENVIRONMENT. 2023 4 538 28 ATHEROSCLEROSIS AND EPIGENETIC MODIFICATIONS IN CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS ONE OF THE MOST COMMON CHRONIC DISEASES WORLDWIDE, WITH PREVALENCE CURRENTLY PROJECTED AT 10% AND RISING. CARDIOVASCULAR DISEASE IS THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN CKD PATIENTS AND IS INTEGRALLY LINKED WITH ATHEROGENESIS AND VASCULAR STIFFNESS. ESTIMATED GLOMERULAR FILTRATION RATE AND THE LEVEL OF PROTEINURIA ARE NOT ONLY MARKERS OF KIDNEY FUNCTION BUT OF CARDIOVASCULAR RISK, AS WELL. DESPITE THE EFFORTS, CKD PATIENTS STILL EXPERIENCE EXCESSIVE CARDIOVASCULAR BURDEN. MICRORNAS (MIRNAS) ARE SMALL (18-24 NUCLEOTIDES), SINGLE-STRANDED NON-CODING RNAS THAT REGULATE GENE EXPRESSION BY BLOCKING MESSENGER RNA (MRNA) TRANSLATION AND INITIATING DEGRADATION OF MRNA. STUDIES HAVE CONFIRMED THE IMPERATIVE ROLE OF MIRNA DYSREGULATION IN THE PATHOPHYSIOLOGY OF SEVERAL DISEASES, INCLUDING ATHEROSCLEROSIS AND CKD. THIS ARTICLE SUMMARIZES WHAT IS CURRENTLY KNOWN ABOUT THE ROLE OF MIRNAS IN CKD PATIENTS. 2023 5 1388 25 DIABETIC PATIENTS WITH CHRONIC KIDNEY DISEASE: NON-INVASIVE ASSESSMENT OF CARDIOVASCULAR RISK. THE PREVALENCE AND BURDEN OF DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE ON GLOBAL HEALTH AND SOCIOECONOMIC DEVELOPMENT IS ALREADY HEAVY AND STILL RISING. DIABETES MELLITUS BY ITSELF IS LINKED TO ADVERSE CARDIOVASCULAR EVENTS, AND THE PRESENCE OF CONCOMITANT CHRONIC KIDNEY DISEASE FURTHER AMPLIFIES CARDIOVASCULAR RISK. THE CULMINATION OF TRADITIONAL (MALE GENDER, SMOKING, ADVANCED AGE, OBESITY, ARTERIAL HYPERTENSION AND DYSLIPIDEMIA) AND NON-TRADITIONAL RISK FACTORS (ANEMIA, INFLAMMATION, PROTEINURIA, VOLUME OVERLOAD, MINERAL METABOLISM ABNORMALITIES, OXIDATIVE STRESS, ETC.) CONTRIBUTES TO ADVANCED ATHEROSCLEROSIS AND INCREASED CARDIOVASCULAR RISK. TO DECREASE THE MORBIDITY AND MORTALITY OF THESE PATIENTS DUE TO CARDIOVASCULAR CAUSES, TIMELY AND EFFICIENT CARDIOVASCULAR RISK ASSESSMENT IS OF HUGE IMPORTANCE. CARDIOVASCULAR RISK ASSESSMENT CAN BE BASED ON LABORATORY PARAMETERS, IMAGING TECHNIQUES, ARTERIAL STIFFNESS PARAMETERS, ANKLE-BRACHIAL INDEX AND 24 H BLOOD PRESSURE MEASUREMENTS. NEWER METHODS INCLUDE EPIGENETIC MARKERS, SOLUBLE ADHESION MOLECULES, CYTOKINES AND MARKERS OF OXIDATIVE STRESS. IN THIS REVIEW, THE AUTHORS PRESENT SEVERAL NON-INVASIVE METHODS OF CARDIOVASCULAR RISK ASSESSMENT IN PATIENTS WITH DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE. 2021 6 6774 41 [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 7 484 26 ARTICULAR CARTILAGE CHANGES IN MATURING ATHLETES: NEW TARGETS FOR JOINT REJUVENATION. CONTEXT: ARTICULAR CARTILAGE HAS A UNIQUE FUNCTIONAL ARCHITECTURE CAPABLE OF PROVIDING A LIFETIME OF PAIN-FREE JOINT MOTION. THIS TISSUE, HOWEVER, UNDERGOES SUBSTANTIAL AGE-RELATED PHYSIOLOGIC, MECHANICAL, BIOCHEMICAL, AND FUNCTIONAL CHANGES THAT REDUCE ITS ABILITY TO OVERCOME THE EFFECTS OF MECHANICAL STRESS AND INJURY. MANY FACTORS AFFECT JOINT FUNCTION IN THE MATURING ATHLETE-FROM CHONDROCYTE SURVIVAL AND METABOLISM TO STRUCTURAL COMPOSITION AND GENETIC/EPIGENETIC FACTORS GOVERNING CARTILAGE AND SYNOVIUM. AN EVALUATION OF AGE-RELATED CHANGES FOR JOINT HOMEOSTASIS AND RISK FOR OSTEOARTHRITIS IS IMPORTANT TO THE DEVELOPMENT OF NEW STRATEGIES TO REJUVENATE AGING JOINTS. OBJECTIVE: THIS REVIEW SUMMARIZES THE CURRENT LITERATURE ON THE BIOCHEMICAL, CELLULAR, AND PHYSIOLOGIC CHANGES OCCURRING IN AGING ARTICULAR CARTILAGE. DATA SOURCES: PUBMED (1969-2013) AND PUBLISHED BOOKS IN SPORTS HEALTH, CARTILAGE BIOLOGY, AND AGING. STUDY SELECTION: KEYWORDS INCLUDED AGING, ATHLETE, ARTICULAR CARTILAGE, EPIGENETICS, AND FUNCTIONAL PERFORMANCE WITH AGE. STUDY DESIGN: SYSTEMATIC REVIEW. LEVEL OF EVIDENCE: LEVEL 3. DATA EXTRACTION: TO BE INCLUDED, RESEARCH QUESTIONS ADDRESSED THE EFFECT OF AGE-RELATED CHANGES ON PERFORMANCE, ARTICULAR CARTILAGE BIOLOGY, MOLECULAR MECHANISM, AND MORPHOLOGY. RESULTS: THE MATURE ATHLETE FACES CHALLENGES IN MAINTAINING CARTILAGE HEALTH AND JOINT FUNCTION DUE TO AGE-RELATED CHANGES TO ARTICULAR CARTILAGE BIOLOGY, MORPHOLOGY, AND PHYSIOLOGY. THESE CHANGES INCLUDE CHONDROCYTE LOSS AND A DECLINE IN METABOLIC RESPONSE, ALTERATIONS TO MATRIX AND SYNOVIAL TISSUE COMPOSITION, AND DYSREGULATION OF REPARATIVE RESPONSES. CONCLUSION: ALTHOUGH PHYSICAL DECLINE HAS BEEN REGARDED AS A NORMAL PART OF AGING, MANY INDIVIDUALS MAINTAIN OVERALL FITNESS AND ENJOY TARGETED IMPROVEMENT TO THEIR ATHLETIC CAPACITY THROUGHOUT LIFE. HEALTHY ARTICULAR CARTILAGE AND JOINTS ARE NEEDED TO MAINTAIN ATHLETIC PERFORMANCE AND GENERAL ACTIVITIES. GENETIC AND POTENTIALLY REVERSIBLE EPIGENETIC FACTORS INFLUENCE CARTILAGE PHYSIOLOGY AND ITS RESPONSE TO MECHANICAL AND INJURIOUS STIMULI. IMPROVED UNDERSTANDINGS OF THE PHYSICAL AND MOLECULAR CHANGES TO ARTICULAR CARTILAGE WITH AGING ARE IMPORTANT TO DEVELOP SUCCESSFUL STRATEGIES FOR JOINT REJUVENATION. 2014 8 1047 25 CLINICAL EFFECT AND BIOLOGICAL MECHANISM OF EXERCISE FOR RHEUMATOID ARTHRITIS: A MINI REVIEW. RHEUMATOID ARTHRITIS (RA) IS A COMMON SYSTEMATIC, CHRONIC INFLAMMATORY, AUTOIMMUNE, AND POLYARTICULAR DISEASE, CAUSING A RANGE OF CLINICAL MANIFESTATIONS, INCLUDING JOINT SWELLING, REDNESS, PAIN, STIFFNESS, FATIGUE, DECREASED QUALITY OF LIFE, PROGRESSIVE DISABILITY, CARDIOVASCULAR PROBLEMS, AND OTHER COMORBIDITIES. STRONG EVIDENCE HAS SHOWN THAT EXERCISE IS EFFECTIVE FOR RA TREATMENT IN VARIOUS CLINICAL DOMAINS. EXERCISE TRAINING FOR RELATIVELY LONGER PERIODS (E.G., >/= 12 WEEKS) CAN DECREASE DISEASE ACTIVITY OF RA. HOWEVER, THE MECHANISM UNDERLYING THE EFFECTIVENESS OF EXERCISE IN REDUCING RA DISEASE ACTIVITY REMAINS UNCLEAR. THIS REVIEW FIRST SUMMARIZES AND HIGHLIGHTS THE EFFECTIVENESS OF EXERCISE IN RA TREATMENT. THEN, WE INTEGRATE CURRENT EVIDENCE AND PROPOSE BIOLOGICAL MECHANISMS RESPONSIBLE FOR THE POTENTIAL EFFECTS OF EXERCISE ON IMMUNE CELLS AND IMMUNITY, INFLAMMATORY RESPONSE, MATRIX METALLOPROTEINASES, OXIDATIVE STRESS, AND EPIGENETIC REGULATION. HOWEVER, A LARGE BODY OF EVIDENCE WAS OBTAINED FROM THE NON-RA POPULATIONS. FUTURE STUDIES ARE NEEDED TO FURTHER EXAMINE THE PROPOSED BIOLOGICAL MECHANISMS RESPONSIBLE FOR THE EFFECTIVENESS OF EXERCISE IN DECREASING DISEASE ACTIVITY IN RA POPULATIONS. SUCH KNOWLEDGE WILL CONTRIBUTE TO THE BASIC SCIENCE AND STRENGTHEN THE SCIENTIFIC BASIS OF THE PRESCRIPTION OF EXERCISE THERAPY FOR RA IN THE CLINICAL ROUTINE. 2022 9 6357 30 THE ROLE OF HYPERGLYCAEMIA IN THE DEVELOPMENT OF DIABETIC CARDIOMYOPATHY. DIABETES MELLITUS IS A METABOLIC DISORDER WITH A CHRONIC HYPERGLYCAEMIC STATE. CARDIOVASCULAR DISEASES ARE THE PRIMARY CAUSE OF MORTALITY IN PATIENTS WITH DIABETES. INCREASING EVIDENCE SUPPORTS THE EXISTENCE OF DIABETIC CARDIOMYOPATHY, A CARDIAC DYSFUNCTION WITH IMPAIRED CARDIAC CONTRACTION AND RELAXATION, INDEPENDENT OF CORONARY AND/OR VALVULAR COMPLICATIONS. DIABETIC CARDIOMYOPATHY CAN LEAD TO HEART FAILURE. SEVERAL PRECLINICAL AND CLINICAL STUDIES HAVE AIMED TO DECIPHER THE UNDERLYING MECHANISMS OF DIABETIC CARDIOMYOPATHY. AMONG ALL THE CO-FACTORS, HYPERGLYCAEMIA SEEMS TO PLAY AN IMPORTANT ROLE IN THIS PATHOLOGY. HYPERGLYCAEMIA HAS BEEN SHOWN TO ALTER CARDIAC METABOLISM AND FUNCTION THROUGH SEVERAL DELETERIOUS MECHANISMS, SUCH AS OXIDATIVE STRESS, INFLAMMATION, ACCUMULATION OF ADVANCED GLYCATED END-PRODUCTS AND UPREGULATION OF THE HEXOSAMINE BIOSYNTHESIS PATHWAY. THESE MECHANISMS ARE RESPONSIBLE FOR THE ACTIVATION OF HYPERTROPHIC PATHWAYS, EPIGENETIC MODIFICATIONS, MITOCHONDRIAL DYSFUNCTION, CELL APOPTOSIS, FIBROSIS AND CALCIUM MISHANDLING, LEADING TO CARDIAC STIFFNESS, AS WELL AS CONTRACTILE AND RELAXATION DYSFUNCTION. THIS REVIEW AIMS TO DESCRIBE THE HYPERGLYCAEMIC-INDUCED ALTERATIONS THAT PARTICIPATE IN DIABETIC CARDIOMYOPATHY, AND THEIR CORRELATION WITH THE SEVERITY OF THE DISEASE AND PATIENT MORTALITY, AND TO PROVIDE AN OVERVIEW OF CARDIAC OUTCOMES OF GLUCOSE-LOWERING THERAPY. 2021 10 3512 24 IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. THIS DISEASE WAS ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, BUT CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE IS DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS (AECS). THESE CELLS PRODUCE MEDIATORS THAT INDUCE THE FORMATION OF FIBROBLAST AND MYOFIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF THE EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE MECHANISMS THAT LINK IDIOPATHIC PULMONARY FIBROSIS WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN; EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES HAVE A ROLE. IN THIS SEMINAR, WE REVIEW RECENT DATA ON THE CLINICAL COURSE, THERAPEUTIC OPTIONS, AND UNDERLYING MECHANISMS THOUGHT TO BE INVOLVED IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. 2011 11 5801 29 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 12 6218 21 THE JOINT SYNOVIUM: A CRITICAL DETERMINANT OF ARTICULAR CARTILAGE FATE IN INFLAMMATORY JOINT DISEASES. THE SYNOVIUM CONSTITUTES THE ENVELOPE OF ARTICULAR JOINTS AND IS A CRITICAL PROVIDER OF SYNOVIAL FLUID COMPONENTS AND ARTICULAR CARTILAGE NUTRIENTS. ITS INFLAMMATION IS A PREDOMINANT FEATURE AND CAUSE OF JOINT DEGENERATION IN DISEASES AS DIVERSE AS RHEUMATOID, PSORIATIC, JUVENILE AND IDIOPATHIC ARTHRITIS, AND LUPUS, GOUT AND LYME DISEASE. THESE INFLAMMATORY JOINT DISEASES (IJDS) ARE DUE TO A WIDE VARIETY OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS THAT TRIGGER, PROMOTE, AND PERPETUATE JOINT DESTABILIZATION. IN SPITE OF THIS VARIETY OF CAUSES, IJDS SHARE MAIN PATHOLOGICAL FEATURES, NAMELY INFLAMMATION OF THE JOINT SYNOVIUM (SYNOVITIS) AND PROGRESSIVE DEGENERATION OF ARTICULAR CARTILAGE. IN ADDITION TO BEING A DRIVING FORCE BEHIND THE DESTRUCTION OF ARTICULAR CARTILAGE IN IJD, SYNOVITIS IS ALSO INCREASINGLY BEING RECOGNIZED AS A SIGNIFICANT CONTRIBUTOR OF ARTICULAR CARTILAGE DEGENERATION IN OSTEOARTHRITIS, A DISEASE PRIMARILY DUE TO AGING- OR TRAUMA-RELATED WEAR AND TEAR OF CARTILAGE SURFACES. IN VIEW OF THIS IMPORTANT ROLE OF THE SYNOVIUM IN DETERMINING THE FATE OF ARTICULAR CARTILAGE, THIS REVIEW FOCUSES ON ITS UNDERLYING MECHANISMS IN THE PATHOLOGY OF IJD. WE ADDRESS THE ROLES OF SYNOVIAL FIBROBLASTS, MACROPHAGES AND ENDOTHELIAL CELLS IN THE MAINTENANCE OF JOINT HEALTH AND IN THE DESTRUCTION OF ARTICULAR CARTILAGE INTEGRITY DURING IJD. MOLECULAR MECHANISMS THAT HAVE BEEN RECENTLY SHOWN TO GOVERN THE PATHOLOGICAL ACTIVITIES OF THE RESIDENT SYNOVIAL CELLS ARE HIGHLIGHTED. FINALLY, ADVANTAGES AND DISADVANTAGES OF TARGETING THESE NEW MOLECULAR MECHANISMS FOR PREVENTING CARTILAGE DEGENERATION DUE TO CHRONIC INFLAMMATION ARE ALSO DISCUSSED. 2017 13 6212 21 THE INTERPLAY OF THE GENETIC ARCHITECTURE, AGING, AND ENVIRONMENTAL FACTORS IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC FIBROSING LUNG DISEASE OF INDETERMINATE ETIOLOGY AND LIMITED THERAPEUTIC OPTIONS. THE INITIATION, DEVELOPMENT, AND PROGRESSION OF IPF ARE INFLUENCED BY GENETIC PREDISPOSITION, AGING, AND HOST AND ENVIRONMENTAL FACTORS, BUT THE MAGNITUDE OF THE CONTRIBUTION OF EACH OF THEM AND THE SEQUENCE OF THE PATHOGENIC EVENTS ARE UNCERTAIN. CURRENT EVIDENCE INDICATES THAT ACCUMULATED ENVIRONMENTAL EXPOSURES IN A GENETICALLY PREDISPOSED INDIVIDUAL, USUALLY OVER 60 YEARS OF AGE, LEADS TO PHENOTYPIC AND FUNCTIONAL ALTERATIONS OF THE LUNG EPITHELIUM. ABERRANT ACTIVATION OF EPITHELIAL CELLS RESULTS, THROUGH A COMPLEX RELEASE OF NUMEROUS MEDIATORS, IN THE LOCAL EXPANSION OF PECULIAR SUBSETS OF AGGRESSIVE FIBROBLASTS AND MYOFIBROBLASTS, WHICH ARE CRUCIAL EFFECTOR CELLS OF FIBROTIC REMODELING AND LOSS OF THE NORMAL LUNG ARCHITECTURE AND FUNCTION. PROGRESSIVE INCREASE OF THE MECHANICAL STIFFNESS ACTIVATES CELL-AUTONOMOUS AND MATRIX-DEPENDENT PROCESSES CONTRIBUTING TO THE PERPETUATION OF THE FIBROTIC RESPONSE. THIS PERSPECTIVE PROVIDES AN INTEGRAL OVERVIEW OF THE MAJOR RISK FACTORS UNDERPINNING THE PATHOGENESIS OF IPF, INCLUDING GENE VARIANTS, AGING ALTERATIONS, ENVIRONMENTAL FACTORS, HOST RISK FACTORS, AND EPIGENETIC REPROGRAMMING. 2021 14 3592 37 IMPAIRED VASCULAR FUNCTION CONTRIBUTES TO EXERCISE INTOLERANCE IN CHRONIC KIDNEY DISEASE. BACKGROUND: EXERCISE INTOLERANCE IS AN IMPORTANT FEATURE IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) AND IS PROGNOSTIC FOR BOTH INCREASED MORBIDITY AND MORTALITY. LITTLE IS KNOWN ABOUT THE UNDERLYING MECHANISMS IN PREDIALYSIS CKD. THIS STUDY AIMED TO GAIN MORE INSIGHT INTO THE ROLE OF VASCULAR DYSFUNCTION IN THE EXERCISE INTOLERANCE OF PREDIALYSIS CKD. IN ADDITION, VASCULAR-RELATED MICRORNAS (MIRNAS)-AS EPIGENETIC REGULATORS OF EXERCISE CAPACITY-WERE ANALYSED. METHODS: SIXTY-THREE PATIENTS WITH CKD STAGES 1-5 AND 18 HEALTHY CONTROLS WERE INCLUDED. PEAK OXYGEN CONSUMPTION (VO(2)PEAK) WAS DETERMINED BY CARDIOPULMONARY EXERCISE TESTING, ENDOTHELIAL FUNCTION BY FLOW-MEDIATED DILATION (FMD) AND ARTERIAL STIFFNESS BY CAROTID-FEMORAL PULSE WAVE VELOCITY (PWV). PLASMA MIRNA LEVELS (MIR-21, MIR-126, MIR-146A, MIR-150 AND MIR-210) WERE QUANTIFIED BY QUANTITATIVE RT-PCR. RESULTS: VO(2)PEAK WAS ALREADY IMPAIRED IN MILD CKD (STAGES 1-3A) AND SIGNIFICANTLY CORRELATED WITH ESTIMATED GLOMERULAR FILTRATION RATE (EGFR; R = 0.525, P < 0.001). LIKEWISE, BOTH FMD AND PWV WERE SIGNIFICANTLY CORRELATED WITH EGFR (R = 0.319, P = 0.007 AND R = -0.365, P = 0.001, RESPECTIVELY). IN MULTIPLE REGRESSION ANALYSIS, PWV REMAINED ONE OF THE STRONGEST INDEPENDENT DETERMINANTS OF VO(2)PEAK (BETA = -0.301, P = 0.01). OF THE STUDIED MIRNA, CIRCULATING LEVELS OF MIR-146A AND MIR-150 CORRELATED WITH EGFR, PWV AND VO(2)PEAK, BUT THE ASSOCIATION WITH THE LATTER WAS LOST WHEN CORRECTING FOR PWV. CONCLUSIONS: ARTERIAL STIFFNESS CONTRIBUTES TO THE OBSERVED REDUCED AEROBIC CAPACITY IN PREDIALYSIS CKD, INDEPENDENT OF AGE, HAEMOGLOBIN LEVELS AND ENDOTHELIAL FUNCTION AND REPRESENTS A PROMISING THERAPEUTIC TARGET FOR IMPROVING EXERCISE CAPACITY IN THIS POPULATION. FUTURE WORK IS REQUIRED TO ELUCIDATE WHY HIGHER CIRCULATING LEVELS OF MIR-146A AND MIR-150 ARE ASSOCIATED WITH IMPAIRED RENAL FUNCTION AND INCREASED ARTERIAL STIFFNESS. 2016 15 4467 29 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 16 3674 24 INFLAMMATION AND DYSREGULATED FIBROBLAST PROLIFERATION--NEW MECHANISMS? IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE MAY PRIMARILY BE DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS AND THE UNDERLYING MESENCHYME. THE MEDIATORS PRODUCED AND PRESENT IN THIS MICROENVIRONMENT INDUCE THE FORMATION OF FIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE DETAILED MECHANISMS THAT LINK IPF WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN, BUT SOME EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES MAY PLAY A ROLE. THIS REVIEW PROVIDES A BRIEF SYNOPSIS OF HIGHLIGHTS IN THE CURRENT UNDERSTANDING OF THE PATHOPHYSIOLOGY OF IPF, AS WELL AS NOVEL THERAPEUTICS BEING EXPLORED IN CLINICAL TRIALS FOR THE TREATMENT OF THIS DEVASTATING DISEASE. 2013 17 4954 19 PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ENCOMPASSES A NUMBER OF INJURIOUS PROCESSES, INCLUDING AN ABNORMAL INFLAMMATORY RESPONSE IN THE LUNGS TO INHALED PARTICLES AND GASES. OTHER PROCESSES, SUCH AS FAILURE TO RESOLVE INFLAMMATION, ABNORMAL CELL REPAIR, APOPTOSIS, ABNORMAL CELLULAR MAINTENANCE PROGRAMS, EXTRACELLULAR MATRIX DESTRUCTION (PROTEASE/ANTIPROTEASE IMBALANCE), AND OXIDATIVE STRESS (OXIDANT/ANTIOXIDANT IMBALANCE) ALSO HAVE A ROLE. THE INFLAMMATORY RESPONSES TO THE INHALATION OF ACTIVE AND PASSIVE TOBACCO SMOKE AND URBAN AND RURAL AIR POLLUTION ARE MODIFIED BY GENETIC AND EPIGENETIC FACTORS. THE SUBSEQUENT CHRONIC INFLAMMATORY RESPONSES LEAD TO MUCUS HYPERSECRETION, AIRWAY REMODELING, AND ALVEOLAR DESTRUCTION. THIS ARTICLE PROVIDES AN UPDATE ON THE CELLULAR AND MOLECULAR MECHANISMS OF THESE PROCESSES IN THE PATHOGENESIS OF COPD. 2007 18 2554 30 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 19 6786 28 [CONSENSUS AND CONTROVERSY ON RESEARCH PROGRESS AND CLINICAL PRACTICE OF VASCULAR CALCIFICATION]. VASCULAR CALCIFICATION IS AN ACTIVE AND COMPLEX PATHOLOGICAL PROCESS REGULATED BY SEVERAL FACTORS. VASCULAR CALCIFICATION IS CLOSELY RELATED TO THE INCIDENCE AND MORTALITY OF THE CARDIOVASCULAR DISEASE, CHRONIC KIDNEY DISEASE AND OTHER DISEASES, WHICH AFFECTS MULTIPLE ORGANS AND SYSTEMS, THUS AFFECTING PEOPLE'S HEALTH. THEREFORE, MORE AND MORE ATTENTION IS PAID TO VASCULAR CALCIFICATION. AT PRESENT, THE PATHOGENESIS AND CLINICAL PRACTICE OF VASCULAR CALCIFICATION HAVE BEEN CONTINUOUSLY IMPROVED, WHICH MAINLY INCLUDES CALCIUM AND PHOSPHORUS IMBALANCE THEORY, VASCULAR SMOOTH MUSCLE CELL TRANSDIFFERENTIATION THEORY, BONE HOMEOSTASIS IMBALANCE THEORY, EPIGENETIC REGULATION THEORY, INFLAMMATION THEORY, EXTRACELLULAR MATRIX THEORY, NEW CELL FATE THEORY AND SO ON. HOWEVER, THERE ARE STILL MANY UNSOLVED PROBLEMS. SINCE THE OCCURRENCE AND DEVELOPMENT OF VASCULAR CALCIFICATION AFFECT MULTIPLE ORGANS AND SYSTEMS, THIS EXPERT CONSENSUS GATHERED CLINICIANS AND BASIC RESEARCH EXPERTS ENGAGED IN THE STUDY OF VASCULAR CALCIFICATION IN ORDER TO SUMMARIZE THE PROGRESS OF VARIOUS DISCIPLINES RELATED TO VASCULAR CALCIFICATION IN RECENT YEARS. THE PURPOSE OF THIS CONSENSUS IS TO SYSTEMATICALLY SUMMARIZE THE LATEST RESEARCH PROGRESS, TREATMENT CONSENSUS AND CONTROVERSY OF VASCULAR CALCIFICATION FROM THE ASPECTS OF EPIDEMIOLOGY, PATHOGENESIS, PREVENTION AND TREATMENT, SO AS TO PROVIDE THEORETICAL BASIS AND CLINICAL ENLIGHTENMENT FOR IN-DEPTH RESEARCH IN THIS FIELD. 2022 20 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