1 4813 83 OBSTRUCTIVE SLEEP APNEA AND HALLMARKS OF AGING. OBSTRUCTIVE SLEEP APNEA (OSA) IS ONE OF THE MOST COMMON SLEEP DISORDERS. SINCE AGING IS A RISK FACTOR FOR OSA DEVELOPMENT, IT IS EXPECTED THAT ITS PREVALENCE WILL INCREASE WITH THE CURRENT INCREASE IN LIFE SPAN. IN RECENT YEARS, SEVERAL STUDIES HAVE SHOWN THAT OSA POTENTIALLY CONTRIBUTES TO FUNCTIONAL DECLINE, MAINLY PROMPTED BY CHRONIC INTERMITTENT HYPOXIA AND SLEEP FRAGMENTATION. HERE, WE PROPOSE THAT OSA MIGHT ANTICIPATE/AGGRAVATE AGING BY INDUCING CELLULAR AND MOLECULAR IMPAIRMENTS THAT CHARACTERIZE THE AGING PROCESS, SUCH AS STEM CELL EXHAUSTION, TELOMERE ATTRITION AND EPIGENETIC CHANGES. WE SUGGEST THAT FURTHER KNOWLEDGE ON THE IMPACT OF OSA ON AGING MECHANISMS MIGHT CONTRIBUTE TO A BETTER UNDERSTANDING OF HOW OSA MIGHT PUTATIVELY ACCELERATE AGING AND AGING-RELATED DISEASES. 2017 2 443 25 AORTA MACROPHAGE INFLAMMATORY AND EPIGENETIC CHANGES IN A MURINE MODEL OF OBSTRUCTIVE SLEEP APNEA: POTENTIAL ROLE OF CD36. OBSTRUCTIVE SLEEP APNEA (OSA) AFFECTS 8-10% OF THE POPULATION, IS CHARACTERIZED BY CHRONIC INTERMITTENT HYPOXIA (CIH), AND CAUSALLY ASSOCIATES WITH CARDIOVASCULAR MORBIDITIES. IN CIH-EXPOSED MICE, CLOSELY MIMICKING THE CHRONICITY OF HUMAN OSA, INCREASED ACCUMULATION AND PROLIFERATION OF PRO-INFLAMMATORY METABOLIC M1-LIKE MACROPHAGES HIGHLY EXPRESSING CD36, EMERGED IN AORTA. TRANSCRIPTOMIC AND MEDIP-SEQ APPROACHES IDENTIFIED ACTIVATION OF PRO-ATHEROGENIC PATHWAYS INVOLVING A COMPLEX INTERPLAY OF HISTONE MODIFICATIONS IN FUNCTIONALLY-RELEVANT BIOLOGICAL PATHWAYS, SUCH AS INFLAMMATION AND OXIDATIVE STRESS IN AORTA MACROPHAGES. DISCONTINUATION OF CIH DID NOT ELICIT SIGNIFICANT IMPROVEMENTS IN AORTA WALL MACROPHAGE PHENOTYPE. HOWEVER, CIH-INDUCED AORTA CHANGES WERE ABSENT IN CD36 KNOCKOUT MICE, OUR RESULTS PROVIDE MECHANISTIC INSIGHTS SHOWING THAT CIH EXPOSURES DURING SLEEP IN ABSENCE OF CONCURRENT PRO-ATHEROGENIC SETTINGS (I.E., GENETIC PROPENSITY OR DIETARY MANIPULATION) LEAD TO THE RECRUITMENT OF CD36(+)(HIGH) MACROPHAGES TO THE AORTIC WALL AND TRIGGER ATHEROGENESIS. FURTHERMORE, LONG-TERM CIH-INDUCED CHANGES MAY NOT BE REVERSIBLE WITH USUAL OSA TREATMENT. 2017 3 231 22 ADAPTIVE CARDIORESPIRATORY CHANGES TO CHRONIC CONTINUOUS AND INTERMITTENT HYPOXIA. THIS CHAPTER REVIEWS CARDIORESPIRATORY ADAPTATIONS TO CHRONIC HYPOXIA (CH) EXPERIENCED AT HIGH ALTITUDE AND CARDIORESPIRATORY PATHOLOGIES ELICITED BY CHRONIC INTERMITTENT HYPOXIA (CIH) OCCURRING WITH OBSTRUCTIVE SLEEP APNEA (OSA). SHORT-TERM CH INCREASES BREATHING (VENTILATORY ACCLIMATIZATION TO HYPOXIA) AND BLOOD PRESSURE (BP) THROUGH CAROTID BODY (CB) CHEMO REFLEX. HYPERPLASIA OF GLOMUS CELLS, ALTERATIONS IN ION CHANNELS, AND RECRUITMENT OF ADDITIONAL EXCITATORY MOLECULES ARE IMPLICATED IN THE HEIGHTENED CB CHEMO REFLEX BY CH. TRANSCRIPTIONAL ACTIVATION OF HYPOXIA-INDUCIBLE FACTORS (HIF-1 AND 2) IS A MAJOR MOLECULAR MECHANISM UNDERLYING RESPIRATORY ADAPTATIONS TO SHORT-TERM CH. HIGH-ALTITUDE NATIVES EXPERIENCING LONG-TERM CH EXHIBIT BLUNTED HYPOXIC VENTILATORY RESPONSE (HVR) AND REDUCED BP DUE TO DESENSITIZATION OF CB RESPONSE TO HYPOXIA AND IMPAIRED PROCESSING OF CB SENSORY INFORMATION AT THE CENTRAL NERVOUS SYSTEM. VENTILATORY CHANGES EVOKED BY LONG-TERM CH ARE NOT READILY REVERSED AFTER RETURN TO SEA LEVEL. OSA PATIENTS AND RODENTS SUBJECTED TO CIH EXHIBIT HEIGHTENED CB CHEMO REFLEX, INCREASED HYPOXIC VENTILATORY RESPONSE, AND HYPERTENSION. INCREASED GENERATION OF REACTIVE OXYGEN SPECIES (ROS) IS A MAJOR CELLULAR MECHANISM UNDERLYING CIH-INDUCED ENHANCED CB CHEMO REFLEX AND THE ENSUING CARDIORESPIRATORY PATHOLOGIES. ROS GENERATION BY CIH IS MEDIATED BY NONTRANSCRIPTIONAL, DISRUPTED HIF-1 AND HIF-2-DEPENDENT TRANSCRIPTIONS AS WELL AS EPIGENETIC MECHANISMS. 2022 4 4814 29 OBSTRUCTIVE SLEEP APNEA, CIRCADIAN CLOCK DISRUPTION, AND METABOLIC CONSEQUENCES. OBSTRUCTIVE SLEEP APNEA (OSA) IS A CHRONIC DISORDER CHARACTERIZED BY RECURRENT EPISODES OF APNEA AND HYPOPNEA DURING SLEEP. IT IS ASSOCIATED WITH VARIOUS CARDIOVASCULAR AND METABOLIC COMPLICATIONS, INCLUDING TYPE 2 DIABETES MELLITUS (T2DM) AND OBESITY. MANY PATHWAYS CAN BE RESPONSIBLE FOR T2DM DEVELOPMENT IN OSA PATIENTS, E.G., THOSE RELATED TO HIF-1 AND SIRT1 EXPRESSION. MOREOVER, EPIGENETIC MECHANISMS, SUCH AS MIRNA181A OR MIRNA199, ARE POSTULATED TO PLAY A PIVOTAL ROLE IN THIS LINK. IT HAS BEEN PROVEN THAT OSA INCREASES THE OCCURRENCE OF CIRCADIAN CLOCK DISRUPTION, WHICH IS ALSO A RISK FACTOR FOR METABOLIC DISEASE DEVELOPMENT. CIRCADIAN CLOCK DISRUPTION IMPAIRS THE METABOLISM OF GLUCOSE, LIPIDS, AND THE SECRETION OF BILE ACIDS. THEREFORE, OSA-INDUCED CIRCADIAN CLOCK DISRUPTION MAY BE A POTENTIAL, COMPLEX, UNDERLYING PATHWAY INVOLVED IN DEVELOPING AND EXACERBATING METABOLIC DISEASES AMONG OSA PATIENTS. THE CURRENT PAPER SUMMARIZES THE AVAILABLE INFORMATION PERTAINING TO THE RELATIONSHIP BETWEEN OSA AND CIRCADIAN CLOCK DISRUPTION IN THE CONTEXT OF POTENTIAL MECHANISMS LEADING TO METABOLIC DISORDERS. 2022 5 6420 27 THE THERANOSTIC VALUE OF ACETYLATION GENE SIGNATURES IN OBSTRUCTIVE SLEEP APNEA DERIVED BY MACHINE LEARNING. EPIGENETIC MODIFICATIONS ARE IMPLICATED IN THE ONSET AND PROGRESSION OF OBSTRUCTIVE SLEEP APNEA (OSA) AND ITS COMPLICATIONS THROUGH THEIR BIDIRECTIONAL RELATIONSHIP WITH LONG-TERM CHRONIC INTERMITTENT HYPOXIA (IH). HOWEVER, THE EXACT ROLE OF EPIGENETIC ACETYLATION IN OSA IS UNCLEAR. HERE WE EXPLORED THE RELEVANCE AND IMPACT OF ACETYLATION-RELATED GENES IN OSA BY IDENTIFYING MOLECULAR SUBTYPES MODIFIED BY ACETYLATION IN OSA PATIENTS. TWENTY-NINE SIGNIFICANTLY DIFFERENTIALLY EXPRESSED ACETYLATION-RELATED GENES WERE SCREENED IN A TRAINING DATASET (GSE135917). SIX COMMON SIGNATURE GENES WERE IDENTIFIED USING THE LASSO AND SUPPORT VECTOR MACHINE ALGORITHMS, WITH THE POWERFUL SHAP ALGORITHM USED TO JUDGE THE IMPORTANCE OF EACH IDENTIFIED FEATURE. DSCC1, ACTL6A, AND SHCBP1 WERE BEST CALIBRATED AND DISCRIMINATED OSA PATIENTS FROM NORMAL IN BOTH TRAINING AND VALIDATION (GSE38792) DATASETS. DECISION CURVE ANALYSIS SHOWED THAT PATIENTS COULD BENEFIT FROM A NOMOGRAM MODEL DEVELOPED USING THESE VARIABLES. FINALLY, A CONSENSUS CLUSTERING APPROACH CHARACTERIZED OSA PATIENTS AND ANALYZED THE IMMUNE SIGNATURES OF EACH SUBGROUP. OSA PATIENTS WERE DIVIDED INTO TWO ACETYLATION PATTERNS (HIGHER ACETYLATION SCORES IN GROUP B THAN IN GROUP A) THAT DIFFERED SIGNIFICANTLY IN TERMS OF IMMUNE MICROENVIRONMENT INFILTRATION. THIS IS THE FIRST STUDY TO REVEAL THE EXPRESSION PATTERNS AND KEY ROLE PLAYED BY ACETYLATION IN OSA, LAYING THE FOUNDATION FOR OSA EPITHERAPY AND REFINED CLINICAL DECISION-MAKING. 2023 6 5544 25 ROLE OF EPIGENETIC ABNORMALITIES AND INTERVENTION IN OBSTRUCTIVE SLEEP APNEA TARGET ORGANS. OBSTRUCTIVE SLEEP APNEA (OSA) IS A COMMON CONDITION THAT HAS CONSIDERABLE IMPACTS ON HUMAN HEALTH. EPIGENETICS HAS BECOME A RAPIDLY DEVELOPING AND EXCITING AREA IN BIOLOGY, AND IT IS DEFINED AS HERITABLE ALTERATIONS IN GENE EXPRESSION AND HAS REGULATORY EFFECTS ON DISEASE PROGRESSION. HOWEVER, THE PUBLISHED LITERATURE THAT IS INTEGRATING BOTH OF THEM IS NOT SUFFICIENT. THE PURPOSE OF THIS ARTICLE IS TO EXPLORE THE RELATIONSHIP BETWEEN OSA AND EPIGENETICS AND TO OFFER BETTER DIAGNOSTIC METHODS AND TREATMENT OPTIONS. EPIGENETIC MODIFICATIONS MAINLY MANIFEST AS POST-TRANSLATIONAL MODIFICATIONS IN DNA AND HISTONE PROTEINS AND REGULATION OF NON-CODING RNAS. CHRONIC INTERMITTENT HYPOXIA-MEDIATED EPIGENETIC ALTERATIONS ARE INVOLVED IN THE PROGRESSION OF OSA AND DIVERSE MULTIORGAN INJURIES, INCLUDING CARDIOVASCULAR DISEASE, METABOLIC DISORDERS, PULMONARY HYPERTENSION, NEURAL DYSFUNCTION, AND EVEN TUMORS. THIS ARTICLE PROVIDES DEEPER INSIGHTS INTO THE DISEASE MECHANISM OF OSA AND POTENTIAL APPLICATIONS OF TARGETED DIAGNOSIS, TREATMENT, AND PROGNOSIS IN OSA COMPLICATIONS. 2023 7 4542 31 MURINE MODELS OF SLEEP APNEA: FUNCTIONAL IMPLICATIONS OF ALTERED MACROPHAGE POLARITY AND EPIGENETIC MODIFICATIONS IN ADIPOSE AND VASCULAR TISSUES. OBSTRUCTIVE SLEEP APNEA (OSA) IS A HIGHLY PREVALENT DISEASE ACROSS THE LIFESPAN, IS CHARACTERIZED BY CHRONIC INTERMITTENT HYPOXIA AND SLEEP FRAGMENTATION, AND HAS BEEN INDEPENDENTLY ASSOCIATED WITH SUBSTANTIAL CARDIOMETABOLIC MORBIDITY. HOWEVER, THE REVERSIBILITY OF END-ORGAN MORBIDITY WITH TREATMENT IS NOT ALWAYS APPARENT, SUGGESTING THAT BOTH TISSUE REMODELING AND EPIGENETIC MECHANISMS MAY BE OPERATIONALLY INVOLVED. HERE, WE REVIEW THE CUMULATIVE EVIDENCE FOCUSED AROUND MURINE MODELS OF OSA TO ILLUSTRATE THE TEMPORAL DEPENDENCIES OF CARDIOMETABOLIC DYSFUNCTION AND ITS REVERSIBILITY, AND MORE PARTICULARLY TO DISCUSS THE CRITICAL CONTRIBUTIONS OF TISSUE MACROPHAGES TO ADIPOSE TISSUE INSULIN RESISTANCE AND VASCULAR ATHEROGENESIS. IN ADDITION, WE DESCRIBE INITIAL FINDINGS POTENTIALLY IMPLICATING EPIGENETIC ALTERATIONS IN BOTH THE EMERGENCE OF THE CARDIOMETABOLIC MORBIDITY OF OSA, AND IN ITS REVERSIBILITY WITH TREATMENT. WE ANTICIPATE THAT IMPROVED UNDERSTANDING OF MACROPHAGE BIOLOGY AND EPIGENETICS IN THE CONTEXT OF INTERMITTENT HYPOXIA AND SLEEP FRAGMENTATION WILL LEAD TO DISCOVERY OF NOVEL THERAPEUTIC TARGETS AND IMPROVED CARDIOVASCULAR AND METABOLIC OUTCOMES IN OSA. 2018 8 2585 29 EPIGENETICS OF OBSTRUCTIVE SLEEP APNEA SYNDROME: A SYSTEMATIC REVIEW. STUDY OBJECTIVES: OBSTRUCTIVE SLEEP APNEA (OSA) IS A CHRONIC AND WIDELY PREVALENT DISEASE ASSOCIATED WITH MULTIPLE HEALTH DISORDERS. CURRENT DIAGNOSTIC STRATEGIES FOR OSA ARE LIMITED BECAUSE OF COST, TIME, AND ACCESS. EPIGENETIC SIGNATURES OFFER INSIGHT INTO THE RELATIONSHIPS BETWEEN DISEASE AND ENVIRONMENT AND COULD PLAY A SIGNIFICANT ROLE IN DEVELOPING BOTH DIAGNOSTIC AND THERAPEUTIC TOOLS FOR OSA. IN THE CURRENT STUDY, A SYSTEMATIC LITERATURE SEARCH WAS CONDUCTED TO INVESTIGATE THE EXISTING EVIDENCE OF OSA-ASSOCIATED EPIGENETIC MODIFICATIONS. METHODS: A SYSTEMATIC LITERATURE SEARCH WAS PERFORMED USING ELECTRONIC ACADEMIC DATABASES INCLUDING PUBMED, CINAHL, SCOPUS, EMBASE, EBM REVIEWS, AND WEB OF SCIENCE. HOWEVER, THE CURRENT STUDY FOCUSED ON SCREENING FOR ORIGINAL, ENGLISH-LANGUAGE ARTICLES PERTAINING TO OSA AND ASSOCIATED EPIGENETIC MECHANISMS. TO PRODUCE UNBIASED RESULTS, SCREENING WAS PERFORMED INDEPENDENTLY BY AUTHORS. RESULTS: WE IDENTIFIED 2,944 PUBLICATIONS IN OUR SYSTEMATIC SEARCH. AMONG THEM, 65 RESEARCH ARTICLES WERE RELATED TO OS A-ASSOCIATED DIFFERENTIAL GENE EXPRESSION, GENETIC VARIATION, AND EPIGENETIC MODIFICATIONS. ALTHOUGH THESE 65 ARTICLES WERE CONSIDERED FOR FULL MANUSCRIPT REVIEW, ONLY 12 ARTICLES MET THE CRITERIA OF OSA-ASSOCIATED EPIGENETIC MODIFICATIONS IN HUMAN AND ANIMAL MODELS. HUMAN PATIENTS WITH OSA HAD UNIQUE EPIGENETIC CHANGES COMPARED TO HEALTHY CONTROL PATIENTS AND, INTERESTINGLY, EPIGENETIC SIGNATURES WERE COMMONLY IDENTIFIED IN GENES ASSOCIATED WITH METABOLIC AND INFLAMMATORY PATHWAYS. CONCLUSIONS: ALTHOUGH THE AVAILABLE STUDIES ARE LIMITED, THIS RESEARCH PROVIDES NOVEL INSIGHTS FOR THE DEVELOPMENT OF EPIGENETIC MARKERS FOR THE DIAGNOSIS AND TREATMENT OF OSA. THOROUGH GENOME-WIDE INVESTIGATIONS WILL BE REQUIRED TO DEVELOP COST-EFFECTIVE, ROBUST BIOMARKERS FOR THE IDENTIFICATION OF OSA AMONG CHILDREN AND ADULTS. HERE, WE OFFER A STUDY DESIGN FOR SUCH EFFORTS. CITATION: LEADER BA, KORITALA BSC, MOORE CA, DEAN EG, KOTTYAN LC, SMITH DF. EPIGENETICS OF OBSTRUCTIVE SLEEP APNEA SYNDROME: A SYSTEMATIC REVIEW. J CLIN SLEEP MED. 2021;17(12):2533-2541. 2021 9 3121 29 GESTATIONAL INTERMITTENT HYPOXIA INDUCES ENDOTHELIAL DYSFUNCTION, REDUCES PERIVASCULAR ADIPONECTIN AND CAUSES EPIGENETIC CHANGES IN ADULT MALE OFFSPRING. KEY POINTS: OBSTRUCTIVE SLEEP APNOEA (OSA) IS CHARACTERIZED BY INTERMITTENT HYPOXIA, WHICH CAUSES OXIDATIVE STRESS AND INFLAMMATION AND INCREASES THE RISK OF CARDIOVASCULAR DISEASE. OSA DURING PREGNANCY CAUSES ADVERSE MATERNAL AND FETAL OUTCOMES. THE EFFECTS OF PRE-EXISTING OSA IN PREGNANT WOMEN ON CARDIOMETABOLIC OUTCOMES IN THE OFFSPRING ARE UNKNOWN. WE EVALUATED BASIC METABOLIC PARAMETERS, AS WELL AS AORTIC VASCULAR AND PERIVASCULAR ADIPOSE TISSUE (PVAT) FUNCTION IN RESPONSE TO ADIPONECTIN, AND EXAMINED DNA METHYLATION OF ADIPONECTIN GENE PROMOTER IN PVAT IN 16-WEEK-OLD ADULT OFFSPRING EXPOSED TO GESTATIONAL INTERMITTENT HYPOXIA (GIH). GIH DECREASED BODY WEIGHTS AT WEEK 1 IN BOTH MALE AND FEMALE OFFSPRING, AND CAUSED SUBSEQUENT INCREASES IN BODY WEIGHT AND FOOD CONSUMPTION IN MALE OFFSPRING ONLY. ADULT FEMALE OFFSPRING HAD NORMAL LEVELS OF LIPIDS, GLUCOSE AND INSULIN, WITH NO ENDOTHELIAL DYSFUNCTION. ADULT MALE OFFSPRING EXHIBITED DYSLIPIDAEMIA, INSULIN RESISTANCE AND HYPERLEPTINAEMIA. DECREASED ENDOTHELIAL-DEPENDENT VASODILATATION, LOSS OF ANTI-CONTRACTILE ACTIVITY OF PVAT AND LOW CIRCULATING PVAT ADIPONECTIN LEVELS, AS WELL AS INCREASED PRO-INFLAMMATORY GENE EXPRESSION AND DNA METHYLATION OF ADIPONECTIN GENE PROMOTER, OCCURRED IN ADULT MALE OFFSPRING. OUR RESULTS SUGGEST THAT MALE OFFSPRING OF WOMEN WITH OSA COULD BE AT RISK OF DEVELOPING CARDIOMETABOLIC DISEASE DURING ADULTHOOD. ABSTRACT: PERTURBATIONS DURING PREGNANCY CAN PROGRAM THE OFFSPRING TO DEVELOP CARDIOMETABOLIC DISEASES LATER IN LIFE. OBSTRUCTIVE SLEEP APNOEA (OSA) IS A CHRONIC CONDITION THAT FREQUENTLY AFFECTS PREGNANCIES AND LEADS TO ADVERSE FETAL OUTCOMES. WE ASSESSED THE OFFSPRING OF FEMALE MICE EXPERIENCING GESTATIONAL INTERMITTENT HYPOXIA (GIH), A HALLMARK OF OSA, FOR CHANGES IN METABOLIC PROFILES, AORTIC NITRIC OXIDE (NO)-DEPENDENT RELAXATIONS, PERIVASCULAR ADIPOSE TISSUE (PVAT) ANTI-CONTRACTILE ACTIVITIES AND THE RESPONSES TO ADIPONECTIN, AND DNA METHYLATION OF THE ADIPONECTIN GENE PROMOTER IN PVAT TISSUE. PREGNANT MOUSE DAMS WERE EXPOSED TO INTERMITTENT HYPOXIC CYCLES ( FIO2 21-12%) FOR 18 DAYS. GIH RESULTED IN LOWER BODY WEIGHTS OF PUPS AT WEEK 1, FOLLOWED BY SIGNIFICANT WEIGHT GAIN BY WEEK 16 OF AGE IN MALE BUT NOT FEMALE OFFSPRING. PLASMA LIPIDS, LEPTIN AND INSULIN RESISTANCE WERE HIGHER IN GIH MALE ADULT OFFSPRING. ENDOTHELIUM-DEPENDENT RELAXATION IN RESPONSE TO ACH AND THE ANTI-CONTRACTILE ACTIVITY OF PVAT IN THE ABDOMINAL AORTA WAS REDUCED IN GIH ADULT MALE OFFSPRING. INCUBATION OF ARTERIES FROM GIH ADULT MALE OFFSPRING WITH ADIPONECTIN RESTORED THE ANTI-CONTRACTILE ACTIVITY OF PVAT. BOTH CIRCULATING AND PVAT TISSUE HOMOGENATE LEVELS OF ADIPONECTIN, AS WELL AS GENE EXPRESSION OF ADIPONECTIN IN PVAT, WERE LOWER IN GIH MALE OFFSPRING, ALONG WITH AN INCREASED GENE EXPRESSION OF INFLAMMATORY CYTOKINES. PYROSEQUENCING OF ADIPONECTIN GENE PROMOTER IN PVAT SHOWED INCREASED DNA METHYLATION IN GIH MALE OFFSPRING. OUR RESULTS INDICATE THAT GIH LEADS TO VASCULAR DISEASE IN ADULT MALE OFFSPRING THROUGH PVAT DYSFUNCTION, WHICH WAS ASSOCIATED WITH LOW ADIPONECTIN LEVELS AND EPIGENETIC MODIFICATIONS ON THE ADIPONECTIN GENE PROMOTER. 2019 10 2610 25 EPIGENETICS: A POTENTIAL MECHANISM INVOLVED IN THE PATHOGENESIS OF VARIOUS ADVERSE CONSEQUENCES OF OBSTRUCTIVE SLEEP APNEA. EPIGENETICS IS DEFINED AS THE HERITABLE PHENOTYPIC CHANGES WHICH DO NOT INVOLVE ALTERATIONS IN THE DNA SEQUENCE, INCLUDING HISTONE MODIFICATIONS, NON-CODING RNAS, AND DNA METHYLATION. RECENTLY, MUCH ATTENTION HAS BEEN PAID TO THE ROLE OF HYPOXIA-MEDIATED EPIGENETIC REGULATION IN CANCER, PULMONARY HYPERTENSION, ADAPTATION TO HIGH ALTITUDE, AND CARDIORENAL DISEASE. IN CONTRAST TO SUSTAINED HYPOXIA, CHRONIC INTERMITTENT HYPOXIA WITH RE-OXYGENATION (IHR) PLAYS A MAJOR ROLE IN THE PATHOGENESIS OF VARIOUS ADVERSE CONSEQUENCES OF OBSTRUCTIVE SLEEP APNEA (OSA), RESEMBLING ISCHEMIA RE-PERFUSION INJURY. NEVERTHELESS, THE ROLE OF EPIGENETICS IN THE PATHOGENESIS OF OSA IS CURRENTLY UNDEREXPLORED. THIS REVIEW PROPOSES THAT EPIGENETIC PROCESSES ARE INVOLVED IN THE DEVELOPMENT OF VARIOUS ADVERSE CONSEQUENCES OF OSA BY INFLUENCING ADAPTIVE POTENTIAL AND PHENOTYPIC VARIABILITY UNDER CONDITIONS OF CHRONIC IHR. IMPROVED UNDERSTANDING OF THE INTERACTION BETWEEN GENETIC AND ENVIRONMENTAL FACTORS THROUGH EPIGENETIC REGULATIONS HOLDS GREAT VALUE TO GIVE DEEPER INSIGHT INTO THE MECHANISMS UNDERLYING IHR-RELATED LOW-GRADE INFLAMMATION, OXIDATIVE STRESS, AND SYMPATHETIC HYPERACTIVITY, AND CLARIFY THEIR IMPLICATIONS FOR BIOMEDICAL RESEARCH. 2019 11 2359 26 EPIGENETIC REGULATION OF REDOX STATE MEDIATES PERSISTENT CARDIORESPIRATORY ABNORMALITIES AFTER LONG-TERM INTERMITTENT HYPOXIA. KEY POINTS: THE EFFECTS OF SHORT-TERM (ST; 10 DAYS) AND LONG-TERM (LT; 30 DAYS) INTERMITTENT HYPOXIA (IH) ON BLOOD PRESSURE (BP), BREATHING AND CAROTID BODY (CB) CHEMOSENSORY REFLEX WERE EXAMINED IN ADULT RATS. ST- AND LT-IH TREATED RATS EXHIBITED HYPERTENSION, IRREGULAR BREATHING WITH APNOEA AND AUGMENTED THE CB CHEMOSENSORY REFLEX, WITH ALL THESE RESPONSES BECOMING NORMALIZED DURING RECOVERY FROM ST- BUT NOT FROM LT-IH. THE PERSISTENT CARDIORESPIRATORY RESPONSES TO LT-IH WERE ASSOCIATED WITH ELEVATED REACTIVE OXYGEN SPECIES (ROS) LEVELS IN THE CB AND ADRENAL MEDULLA, WHICH WERE A RESULT OF DNA METHYLATION-DEPENDENT SUPPRESSION OF GENES ENCODING ANTI-OXIDANT ENZYMES (AOES). TREATING RATS WITH DECITABINE EITHER DURING LT-IH OR DURING RECOVERY FROM LT-IH PREVENTED DNA METHYLATION OF AOE GENES, NORMALIZED THE EXPRESSION OF AOE GENES AND ROS LEVELS, REVERSED THE HEIGHTENED CB CHEMOSENSORY REFLEX AND HYPERTENSION, AND ALSO STABILIZED BREATHING. ABSTRACT: RODENTS EXPOSED TO CHRONIC INTERMITTENT HYPOXIA (IH), SIMULATING BLOOD O(2) SATURATION PROFILES DURING OBSTRUCTIVE SLEEP APNOEA (OSA), HAVE BEEN SHOWN TO EXHIBIT A HEIGHTENED CAROTID BODY (CB) CHEMOSENSORY REFLEX AND HYPERTENSION. CB CHEMOSENSORY REFLEX ACTIVATION ALSO RESULTS IN UNSTABLE BREATHING WITH APNOEAS. HOWEVER, THE EFFECT OF CHRONIC IH ON BREATHING IS NOT KNOWN. IN THE PRESENT STUDY, WE EXAMINED THE EFFECTS OF CHRONIC IH ON BREATHING ALONG WITH BLOOD PRESSURE (BP) AND ASSESSED WHETHER THE AUTONOMIC RESPONSES ARE NORMALIZED AFTER RECOVERY FROM CHRONIC IH. STUDIES WERE PERFORMED ON ADULT, MALE, SPRAGUE-DAWLEY RATS EXPOSED TO EITHER SHORT-TERM (ST; 10 DAYS) OR LONG-TERM (LT, 30 DAYS) IH. RATS EXPOSED TO EITHER ST- OR LT-IH EXHIBITED HYPERTENSION, IRREGULAR BREATHING WITH APNOEAS, AN AUGMENTED CB CHEMOSENSORY REFLEX AS INDICATED BY ELEVATED CB NEURAL ACTIVITY AND PLASMA CATECHOLAMINE LEVELS, AND ELEVATED REACTIVE OXYGEN SPECIES (ROS) LEVELS IN THE CB AND ADRENAL MEDULLA (AM). ALL THESE EFFECTS WERE NORMALIZED AFTER RECOVERY FROM ST-IH BUT NOT FROM LT-IH. ANALYSIS OF THE MOLECULAR MECHANISMS UNDERLYING THE PERSISTENT EFFECTS OF LT-IH REVEALED INCREASED DNA METHYLATION OF GENES ENCODING ANTI-OXIDANT ENZYMES (AOES). TREATMENT WITH DECITABINE, A DNA METHYLATION INHIBITOR, EITHER DURING LT-IH OR DURING RECOVERY FROM LT-IH, PREVENTED DNA METHYLATION, NORMALIZED THE EXPRESSION OF AOE GENES, ROS LEVELS, CB CHEMOSENSORY REFLEX AND BP, AND ALSO STABILIZED BREATHING. THESE RESULTS SUGGEST THAT PERSISTENT CARDIORESPIRATORY ABNORMALITIES CAUSED BY LT-IH ARE MEDIATED BY EPIGENETIC RE-PROGRAMMING OF THE REDOX STATE IN THE CB CHEMOSENSORY REFLEX PATHWAY. 2017 12 4138 33 MECHANISMS OF MICROGLIAL ACTIVATION IN MODELS OF INFLAMMATION AND HYPOXIA: IMPLICATIONS FOR CHRONIC INTERMITTENT HYPOXIA. CHRONIC INTERMITTENT HYPOXIA (CIH) IS A HALLMARK OF SLEEP APNOEA, A CONDITION ASSOCIATED WITH DIVERSE CLINICAL DISORDERS. CIH AND SLEEP APNOEA ARE CHARACTERIZED BY INCREASED REACTIVE OXYGEN SPECIES FORMATION, PERIPHERAL AND CNS INFLAMMATION, NEURONAL DEATH AND NEUROCOGNITIVE DEFICITS. FEW STUDIES HAVE EXAMINED THE ROLE OF MICROGLIA, THE RESIDENT CNS IMMUNE CELLS, IN MODELS OF CIH. THUS, LITTLE IS KNOWN CONCERNING THEIR DIRECT CONTRIBUTIONS TO NEUROPATHOLOGY OR THE CELLULAR MECHANISMS REGULATING THEIR ACTIVITIES DURING OR FOLLOWING PATHOLOGICAL CIH. IN THIS REVIEW, WE IDENTIFY GAPS IN KNOWLEDGE REGARDING CIH-INDUCED MICROGLIAL ACTIVATION, AND PROPOSE MECHANISMS BASED ON DATA FROM RELATED MODELS OF HYPOXIA AND/OR HYPOXIA-REOXYGENATION. CIH MAY DIRECTLY AFFECT MICROGLIA, OR MAY HAVE INDIRECT EFFECTS VIA THE PERIPHERY OR OTHER CNS CELLS. PERIPHERAL INFLAMMATION MAY INDIRECTLY ACTIVATE MICROGLIA VIA ENTRY OF PRO-INFLAMMATORY MOLECULES INTO THE CNS, AND/OR ACTIVATION OF VAGAL AFFERENTS THAT TRIGGER CNS INFLAMMATION. CIH-INDUCED RELEASE OF DAMAGE-ASSOCIATED MOLECULAR PATTERNS FROM INJURED CNS CELLS MAY ALSO ACTIVATE MICROGLIA VIA INTERACTIONS WITH PATTERN RECOGNITION RECEPTORS EXPRESSED ON MICROGLIA. FOR EXAMPLE, TOLL-LIKE RECEPTORS ACTIVATE MITOGEN-ACTIVATED PROTEIN KINASE/TRANSCRIPTION FACTOR PATHWAYS REQUIRED FOR MICROGLIAL INFLAMMATORY GENE EXPRESSION. ALTHOUGH EPIGENETIC EFFECTS FROM CIH HAVE NOT YET BEEN STUDIED IN MICROGLIA, POTENTIAL EPIGENETIC MECHANISMS IN MICROGLIAL REGULATION ARE DISCUSSED, INCLUDING MICRORNAS, HISTONE MODIFICATIONS AND DNA METHYLATION. EPIGENETIC EFFECTS CAN OCCUR DURING CIH, OR LONG AFTER IT HAS ENDED. A BETTER UNDERSTANDING OF CIH EFFECTS ON MICROGLIAL ACTIVITIES MAY BE IMPORTANT TO REVERSE CIH-INDUCED NEUROPATHOLOGY IN PATIENTS WITH SLEEP DISORDERED BREATHING. 2016 13 2023 23 EPIGENETIC CHANGES BY DNA METHYLATION IN CHRONIC AND INTERMITTENT HYPOXIA. DNA METHYLATION OF CYTOSINE RESIDUES IS A WELL-STUDIED EPIGENETIC CHANGE, WHICH REGULATES GENE TRANSCRIPTION BY ALTERING ACCESSIBILITY FOR TRANSCRIPTION FACTORS. HYPOXIA IS A PERVASIVE STIMULUS THAT AFFECTS MANY PHYSIOLOGICAL PROCESSES. THE CIRCULATORY AND RESPIRATORY SYSTEMS ADAPT TO CHRONIC SUSTAINED HYPOXIA, SUCH AS THAT ENCOUNTERED DURING A HIGH-ALTITUDE SOJOURN. MANY PEOPLE LIVING AT SEA LEVEL EXPERIENCE CHRONIC INTERMITTENT HYPOXIA (IH) DUE TO SLEEP APNEA, WHICH LEADS TO CARDIOVASCULAR AND RESPIRATORY MALADAPTATION. THIS ARTICLE PRESENTS A BRIEF UPDATE ON EMERGING EVIDENCE SUGGESTING THAT CHANGES IN DNA METHYLATION CONTRIBUTE TO PATHOLOGIES CAUSED BY CHRONIC IH AND POTENTIALLY MEDIATE ADAPTATIONS TO CHRONIC SUSTAINED HYPOXIA BY AFFECTING THE HYPOXIA-INDUCIBLE FACTOR (HIF) SIGNALING PATHWAY. 2017 14 1177 27 CONTROL OF BREATHING AND THE CIRCULATION IN HIGH-ALTITUDE MAMMALS AND BIRDS. HYPOXIA IS AN UNREMITTING STRESSOR AT HIGH ALTITUDES THAT PLACES A PREMIUM ON OXYGEN TRANSPORT BY THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS. PHENOTYPIC PLASTICITY AND GENOTYPIC ADAPTATION AT VARIOUS STEPS IN THE O2 CASCADE COULD HELP OFFSET THE EFFECTS OF HYPOXIA ON CELLULAR O2 SUPPLY IN HIGH-ALTITUDE NATIVES. IN THIS REVIEW, WE WILL DISCUSS THE UNIQUE MECHANISMS BY WHICH VENTILATION, CARDIAC OUTPUT, AND BLOOD FLOW ARE CONTROLLED IN HIGH-ALTITUDE MAMMALS AND BIRDS. ACCLIMATIZATION TO HIGH ALTITUDES LEADS TO SOME CHANGES IN RESPIRATORY AND CARDIOVASCULAR CONTROL THAT INCREASE O2 TRANSPORT IN HYPOXIA (E.G., VENTILATORY ACCLIMATIZATION TO HYPOXIA). HOWEVER, ACCLIMATIZATION OR DEVELOPMENT IN HYPOXIA CAN ALSO MODIFY CARDIORESPIRATORY CONTROL IN WAYS THAT ARE MALADAPTIVE FOR O2 TRANSPORT. HYPOXIA RESPONSES THAT AROSE AS SHORT-TERM SOLUTIONS TO O2 DEPRIVATION (E.G., PERIPHERAL VASOCONSTRICTION) OR REGIONAL VARIATION IN O2 LEVELS IN THE LUNGS (I.E., HYPOXIC PULMONARY VASOCONSTRICTION) ARE DETRIMENTAL AT IN CHRONIC HIGH-ALTITUDE HYPOXIA. EVOLVED CHANGES IN CARDIORESPIRATORY CONTROL HAVE ARISEN IN MANY HIGH-ALTITUDE TAXA, INCLUDING INCREASES IN EFFECTIVE VENTILATION, ATTENUATION OF HYPOXIC PULMONARY VASOCONSTRICTION, AND CHANGES IN CATECHOLAMINE SENSITIVITY OF THE HEART AND SYSTEMIC VASCULATURE. PARALLEL EVOLUTION OF SOME OF THESE CHANGES IN INDEPENDENT HIGHLAND LINEAGES SUPPORTS THEIR ADAPTIVE SIGNIFICANCE. MUCH LESS IS KNOWN ABOUT THE GENOMIC BASES AND POTENTIAL INTERACTIVE EFFECTS OF ADAPTATION, ACCLIMATIZATION, DEVELOPMENTAL PLASTICITY, AND TRANS-GENERATIONAL EPIGENETIC TRANSFER ON CARDIORESPIRATORY CONTROL. FUTURE WORK TO UNDERSTAND THESE VARIOUS INFLUENCES ON BREATHING AND CIRCULATION IN HIGH-ALTITUDE NATIVES WILL HELP ELUCIDATE HOW COMPLEX PHYSIOLOGICAL SYSTEMS CAN BE PUSHED TO THEIR LIMITS TO MAINTAIN CELLULAR FUNCTION IN HYPOXIA. 2015 15 1982 34 EPIGENETIC ALTERATIONS IN PEDIATRIC SLEEP APNEA. PEDIATRIC OBSTRUCTIVE SLEEP APNEA HAS SIGNIFICANT NEGATIVE EFFECTS ON HEALTH AND BEHAVIOR IN CHILDHOOD INCLUDING DEPRESSION, FAILURE TO THRIVE, NEUROCOGNITIVE IMPAIRMENT, AND BEHAVIORAL ISSUES. IT IS STRONGLY ASSOCIATED WITH AN INCREASED RISK FOR CHRONIC ADULT DISEASE SUCH AS OBESITY AND DIABETES, ACCELERATED ATHEROSCLEROSIS, AND ENDOTHELIAL DYSFUNCTION. ACCUMULATING EVIDENCE SUGGESTS THAT ADULT-ONSET NON-COMMUNICABLE DISEASES MAY ORIGINATE FROM EARLY LIFE THROUGH A PROCESS BY WHICH AN INSULT APPLIED AT A CRITICAL DEVELOPMENTAL WINDOW CAUSES LONG-TERM EFFECTS ON THE STRUCTURE OR FUNCTION OF AN ORGANISM. IN RECENT YEARS, THERE HAS BEEN INCREASED INTEREST IN THE ROLE OF EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF ADULT DISEASE SUSCEPTIBILITY. EPIGENETIC MECHANISMS THAT INFLUENCE ADAPTIVE VARIABILITY INCLUDE HISTONE MODIFICATIONS, NON-CODING RNAS, AND DNA METHYLATION. THIS REVIEW WILL HIGHLIGHT WHAT IS CURRENTLY KNOWN ABOUT THE PHENOTYPIC ASSOCIATIONS OF EPIGENETIC MODIFICATIONS IN PEDIATRIC OBSTRUCTIVE SLEEP APNEA AND WILL EMPHASIZE THE IMPORTANCE OF EPIGENETIC CHANGES AS BOTH MODULATORS OF CHRONIC DISEASE AND POTENTIAL THERAPEUTIC TARGETS. 2021 16 4109 23 MECHANISMS AND DRUG THERAPY OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. PULMONARY VASOCONSTRICTION REPRESENTS A PHYSIOLOGICAL ADAPTIVE MECHANISM TO HIGH ALTITUDE. IF EXAGGERATED, HOWEVER, IT IS ASSOCIATED WITH IMPORTANT MORBIDITY AND MORTALITY. RECENT MECHANISTIC STUDIES USING SHORT-TERM ACUTE HIGH ALTITUDE EXPOSURE HAVE PROVIDED INSIGHT INTO THE IMPORTANCE OF DEFECTIVE VASCULAR ENDOTHELIAL AND RESPIRATORY EPITHELIAL NITRIC OXIDE (NO) SYNTHESIS, INCREASED ENDOTHELIN-1 BIOAVAILABILITY, AND OVERACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM IN CAUSING EXAGGERATED HYPOXIC PULMONARY HYPERTENSION IN HUMANS. BASED ON THESE STUDIES, DRUGS THAT INCREASE NO BIOAVAILABILITY, ATTENUATE ENDOTHELIN-1 INDUCED PULMONARY VASOCONSTRICTION, OR PREVENT EXAGGERATED SYMPATHETIC ACTIVATION HAVE BEEN SHOWN TO BE USEFUL FOR THE TREATMENT/PREVENTION OF EXAGGERATED PULMONARY HYPERTENSION DURING ACUTE SHORT-TERM HIGH ALTITUDE EXPOSURE. THE MECHANISMS UNDERPINNING CHRONIC PULMONARY HYPERTENSION IN HIGH ALTITUDE DWELLERS ARE LESS WELL UNDERSTOOD, BUT RECENT EVIDENCE SUGGESTS THAT THEY DIFFER IN SOME ASPECTS FROM THOSE INVOLVED IN SHORT-TERM ADAPTATION TO HIGH ALTITUDE. THESE DIFFERENCES HAVE CONSEQUENCES FOR THE CHOICE OF THE TREATMENT FOR CHRONIC PULMONARY HYPERTENSION AT HIGH ALTITUDE. FINALLY, RECENT DATA INDICATE THAT FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN OFFSPRING OF PREECLAMPSIA AND CHILDREN GENERATED BY ASSISTED REPRODUCTIVE TECHNOLOGIES REPRESENTS A NOVEL AND FREQUENT CAUSE OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. IN ANIMAL MODELS OF FETAL PROGRAMMING OF HYPOXIC PULMONARY HYPERTENSION, EPIGENETIC MECHANISMS PLAY A ROLE, AND TARGETING OF THESE MECHANISMS WITH DRUGS LOWERS PULMONARY ARTERY PRESSURE. IF EPIGENETIC MECHANISMS ALSO ARE OPERATIONAL IN THE FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN HUMANS, SUCH DRUGS MAY BECOME NOVEL TOOLS FOR THE TREATMENT OF HYPOXIC PULMONARY HYPERTENSION. 2013 17 6893 25 [SLEEP AND DEMENTIA]. AGING IS ASSOCIATED WITH CHANGES IN SLEEP STRUCTURE AND CEREBRAL DEPOSITION OF AMYLOID BETA AND TAU PROTEINS. SLEEP DISTURBANCES PRECEDE THE ONSET OF DEMENTIA BY YEARS. COMORBID SLEEP DISORDERS, SUCH AS INSOMNIA AND SLEEP-DISORDERED BREATHING, A FAMILY HISTORY OF DEMENTIA AND EPIGENETIC FACTORS CAN CONTRIBUTE TO THE DEVELOPMENT OF DEMENTIA. THIS ARTICLE EXPLORES THE QUESTION OF THE INTERACTION BETWEEN SLEEP AND DEMENTIA BASED ON THE EXISTING LITERATURE. ALTERATIONS CAUSED BY SLOW WAVE SLEEP LEAD TO CHANGES IN THE GLYMPHATIC CLEARANCE OF AMYLOID BETA, TAU PROTEINS AND OTHER PROTEINS. TRANSIENT AND CHRONIC SLEEP DISORDERS CAUSE DISTURBANCES IN THE BRAIN AREAS RESPONSIBLE FOR COGNITION AND BEHAVIOR. SLEEP-REGULATING BRAIN AREAS ARE THE FIRST TO BE AFFECTED IN THE NEURODEGENERATIVE PROCESS AND ACCELERATE THE RISK OF DEMENTIA. CIRCADIAN AGE-RELATED CHANGES IN AMYLOID BETA AND TAU PROTEINS AFFECT THE AMOUNT AND DEPTH OF SLEEP AND VICE VERSA. AMYLOID BETA IN CEREBROSPINAL FLUID SHOWS AN INVERSE CORRELATION WITH SLEEP. OREXINS MODULATE AMYLOID BETA AND SLEEP. 2023 18 5048 34 PHARMACOLOGICAL APPROACHES IN EITHER INTERMITTENT OR PERMANENT HYPOXIA: A TALE OF TWO EXPOSURES. HYPOXIA INDUCES SEVERAL RESPONSES AT CARDIOVASCULAR, PULMONARY AND REPRODUCTIVE LEVELS, WHICH MAY LEAD TO CHRONIC DISEASES. THIS IS RELEVANT IN HUMAN POPULATIONS EXPOSED TO HIGH ALTITUDE (HA), IN EITHER CHRONIC CONTINUOUS (PERMANENT INHABITANTS) OR INTERMITTENT FASHION (HA WORKERS, TOURISTS AND MOUNTAINEERS). IN CHILE, IT IS ESTIMATED THAT 1.000.000 PEOPLE LIVE AT HIGHLANDS AND MORE THAN 55.000 WORK IN HA SHIFTS. INITIAL RESPONSES TO HYPOXIA ARE COMPENSATORY AND INDUCE ACTIVATION OF CARDIOPROTECTIVE MECHANISMS, SUCH AS THOSE SEEN UNDER INTERMITTENT HYPOBARIC (IH) HYPOXIA, EVENTS THAT COULD MEDIATE PRECONDITIONING. HOWEVER, WHENEVER HYPOXIA IS PROLONGED, THE CHRONIC ACTIVATION OF CELLULAR RESPONSES INDUCES LONG-LASTING MODIFICATIONS THAT MAY RESULT IN ACCLIMATIZATION OR PRODUCE MALADAPTIVE CHANGES WITH INCREASE IN CARDIOVASCULAR RISK. HA EXPOSURE DURING PREGNANCY INDUCES HYPOXIA AND OXIDATIVE STRESS, WHICH IN TURN MAY PROMOTE CELLULAR RESPONSES AND EPIGENETIC MODIFICATIONS RESULTING IN SEVERE IMPAIRMENT IN GROWTH AND DEVELOPMENT. SADLY, THIS CONDITION IS ACCOMPANIED WITH AN INCREASED FETAL AND NEONATAL MORBI-MORTALITY. FURTHER, DEVELOPMENTAL HYPOXIA MAY PROGRAM CARDIO-PULMONARY CIRCULATIONS LATER IN POSTNATAL LIFE, ENDING IN VASCULAR STRUCTURAL AND FUNCTIONAL ALTERATIONS WITH AUGMENTED RISK ON PULMONARY AND CARDIOVASCULAR FAILURE. ADDITIONALLY, PERMANENT HA INHABITANTS HAVE AUGMENTED RISK AND PREVALENCE OF CHRONIC HYPOXIC PULMONARY HYPERTENSION, RIGHT VENTRICULAR HYPERTROPHY AND CARDIOPULMONARY REMODELING. SIMILAR RESPONSES ARE SEEN IN ADULTS THAT ARE INTERMITTENTLY EXPOSED TO CHRONIC HYPOXIA (CH) SUCH AS SHIFT WORKERS IN HA AREAS. THE MECHANISMS INVOLVED DETERMINING THE IMMEDIATE, SHORT AND LONG-LASTING EFFECTS ARE STILL UNCLEAR. FOR SEVERAL YEARS, THE STUDY OF THE RESPONSES TO HYPOXIC INSULTS AND PHARMACOLOGICAL TARGETS HAS BEEN THE MOTIVATION OF OUR GROUP. THIS REVIEW DESCRIBES SOME OF THE MECHANISMS UNDERLYING HYPOXIC RESPONSES AND POTENTIAL THERAPEUTIC APPROACHES WITH ANTIOXIDANTS SUCH AS MELATONIN, ASCORBATE, OMEGA 3 (OMEGA3) OR COMPOUNDS THAT INCREASE THE NITRIC OXIDE (NO) BIOAVAILABILITY. 2015 19 4197 20 METABOLIC PROFILES IN OVINE CAROTID ARTERIES WITH DEVELOPMENTAL MATURATION AND LONG-TERM HYPOXIA. BACKGROUND: LONG-TERM HYPOXIA (LTH) IS AN IMPORTANT STRESSOR RELATED TO HEALTH AND DISEASE DURING DEVELOPMENT. AT DIFFERENT TIME POINTS FROM FETUS TO ADULT, WE ARE EXPOSED TO HYPOXIC STRESS BECAUSE OF PLACENTAL INSUFFICIENCY, HIGH-ALTITUDE RESIDENCE, SMOKING, CHRONIC ANEMIA, PULMONARY, AND HEART DISORDERS, AS WELL AS CANCERS. INTRAUTERINE HYPOXIA CAN LEAD TO FETAL GROWTH RESTRICTION AND LONG-TERM SEQUELAE SUCH AS COGNITIVE IMPAIRMENTS, HYPERTENSION, CARDIOVASCULAR DISORDERS, DIABETES, AND SCHIZOPHRENIA. SIMILARLY, PROLONGED HYPOXIC EXPOSURE DURING ADULT LIFE CAN LEAD TO ACUTE MOUNTAIN SICKNESS, CHRONIC FATIGUE, CHRONIC HEADACHE, COGNITIVE IMPAIRMENT, ACUTE CEREBRAL AND/OR PULMONARY EDEMA, AND DEATH. AIM: LTH ALSO CAN LEAD TO ALTERATION IN METABOLITES SUCH AS FUMARATE, 2-OXOGLUTARATE, MALATE, AND LACTATE, WHICH ARE LINKED TO EPIGENETIC REGULATION OF GENE EXPRESSION. IMPORTANTLY, DURING THE INTRAUTERINE LIFE, A FETUS IS UNDER A RELATIVE HYPOXIC ENVIRONMENT, AS COMPARED TO NEWBORN OR ADULT. THUS, THE CHANGES IN GENE EXPRESSION WITH DEVELOPMENT FROM FETUS TO NEWBORN TO ADULT MAY BE AS A CONSEQUENCE OF UNDERLYING CHANGES IN THE METABOLIC PROFILE BECAUSE OF THE HYPOXIC ENVIRONMENT ALONG WITH DEVELOPMENTAL MATURATION. TO EXAMINE THIS POSSIBILITY, WE EXAMINED THE METABOLIC PROFILE IN CAROTID ARTERIES FROM NEAR-TERM FETUS, NEWBORN, AND ADULT SHEEP IN BOTH NORMOXIC AND LONG-TERM HYPOXIC ACCLIMATIZED GROUPS. RESULTS: OUR RESULTS DEMONSTRATE THAT LTH DIFFERENTIALLY REGULATED GLUCOSE METABOLISM, MITOCHONDRIAL METABOLISM, NICOTINAMIDE COFACTOR METABOLISM, OXIDATIVE STRESS AND ANTIOXIDANTS, MEMBRANE LIPID HYDROLYSIS, AND FREE FATTY ACID METABOLISM, EACH OF WHICH MAY PLAY A ROLE IN GENETIC-EPIGENETIC REGULATION. 2015 20 2738 25 EXPOSOMES TO EXOSOMES: EXOSOMES AS TOOLS TO STUDY EPIGENETIC ADAPTIVE MECHANISMS IN HIGH-ALTITUDE HUMANS. HUMANS ON EARTH INHABIT A WIDE RANGE OF ENVIRONMENTAL CONDITIONS AND SOME ENVIRONMENTS ARE MORE CHALLENGING FOR HUMAN SURVIVAL THAN OTHERS. HOWEVER, MANY LIVING BEINGS, INCLUDING HUMANS, HAVE DEVELOPED ADAPTIVE MECHANISMS TO LIVE IN SUCH INHOSPITABLE, HARSH ENVIRONMENTS. AMONG DIFFERENT DIFFICULT ENVIRONMENTS, HIGH-ALTITUDE LIVING IS ESPECIALLY DEMANDING BECAUSE OF DIMINISHED PARTIAL PRESSURE OF OXYGEN AND RESULTING CHRONIC HYPOBARIC HYPOXIA. THIS RESULTS IN POOR BLOOD OXYGENATION AND REDUCES AEROBIC OXIDATIVE RESPIRATION IN THE MITOCHONDRIA, LEADING TO INCREASED REACTIVE OXYGEN SPECIES GENERATION AND ACTIVATION OF HYPOXIA-INDUCIBLE GENE EXPRESSION. GENETIC MECHANISMS IN THE ADAPTATION TO HIGH ALTITUDE IS WELL-STUDIED, BUT THERE ARE ONLY LIMITED STUDIES REGARDING THE ROLE OF EPIGENETIC MECHANISMS. THE PURPOSE OF THIS REVIEW IS TO UNDERSTAND THE EPIGENETIC MECHANISMS BEHIND HIGH-ALTITUDE ADAPTIVE AND MALADAPTIVE PHENOTYPES. HYPOBARIC HYPOXIA IS A FORM OF CELLULAR HYPOXIA, WHICH IS SIMILAR TO THE ONE SUFFERED BY CRITICALLY-ILL HYPOXEMIA PATIENTS. THUS, UNDERSTANDING THE ADAPTIVE EPIGENETIC SIGNALS OPERATING IN IN HIGH-ALTITUDE ADJUSTED INDIGENOUS POPULATIONS MAY HELP IN THERAPEUTICALLY MODULATING SIGNALING PATHWAYS IN HYPOXEMIA PATIENTS BY COPYING THE MOST SUCCESSFUL EPIGENOTYPE. IN ADDITION, WE HAVE SUMMARIZED THE CURRENT INFORMATION ABOUT EXOSOMES IN HYPOXIA RESEARCH AND PROSPECTS TO USE THEM AS DIAGNOSTIC TOOLS TO STUDY THE EPIGENOME OF HIGH-ALTITUDE ADAPTED HEALTHY OR MALADAPTED INDIVIDUALS. 2021