1 231 116 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 2 1177 34 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 3 4109 29 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 4 2738 34 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 5 5048 33 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 6 3428 25 HUMANS AT HIGH ALTITUDE: HYPOXIA AND FETAL GROWTH. HIGH-ALTITUDE STUDIES OFFER INSIGHT INTO THE EVOLUTIONARY PROCESSES AND PHYSIOLOGICAL MECHANISMS AFFECTING THE EARLY PHASES OF THE HUMAN LIFESPAN. CHRONIC HYPOXIA SLOWS FETAL GROWTH AND REDUCES THE PREGNANCY-ASSOCIATED RISE IN UTERINE ARTERY (UA) BLOOD FLOW. MULTIGENERATIONAL VS. SHORTER-TERM HIGH-ALTITUDE RESIDENTS ARE PROTECTED FROM THE ALTITUDE-ASSOCIATED REDUCTIONS IN UA FLOW AND FETAL GROWTH. PRESENTLY UNKNOWN IS WHETHER THIS FETAL-GROWTH PROTECTION IS DUE TO THE GREATER DELIVERY OR METABOLISM OF OXYGEN, GLUCOSE OR OTHER SUBSTRATES OR TO OTHER CONSIDERATIONS SUCH AS MECHANICAL FACTORS PROTECTING FRAGILE FETAL VILLI, THE CREATION OF A RESERVE PROTECTING AGAINST ISCHEMIA/REPERFUSION INJURY, OR IMPROVED PLACENTAL O(2) TRANSFER AS THE RESULT OF NARROWING THE A-V O(2) DIFFERENCE AND RAISING UTERINE P(V)O(2). PLACENTAL GROWTH AND DEVELOPMENT APPEAR TO BE NORMAL OR MODIFIED AT HIGH ALTITUDE IN WAYS LIKELY TO BENEFIT DIFFUSION. MUCH REMAINS TO BE LEARNED CONCERNING THE EFFECTS OF CHRONIC HYPOXIA ON EMBRYONIC DEVELOPMENT. FURTHER RESEARCH IS REQUIRED FOR IDENTIFYING THE FETOPLACENTAL AND MATERNAL MECHANISMS RESPONSIBLE FOR TRANSFORMING THE MATERNAL VASCULATURE AND REGULATING UA BLOOD FLOW AND FETAL GROWTH. GENOMIC AS WELL AS EPIGENETIC STUDIES ARE OPENING NEW AVENUES OF INVESTIGATION THAT CAN YIELD INSIGHTS INTO THE BASIC PATHWAYS AND EVOLUTIONARY PROCESSES INVOLVED. 2011 7 5321 26 PULMONARY ARTERY SMOOTH MUSCLE CELL PROLIFERATION AND MIGRATION IN FETAL LAMBS ACCLIMATIZED TO HIGH-ALTITUDE LONG-TERM HYPOXIA: ROLE OF HISTONE ACETYLATION. HIGH-ALTITUDE LONG-TERM HYPOXIA (LTH) IS KNOWN TO INDUCE PULMONARY ARTERIAL SMOOTH MUSCLE CELL (PASMC) PROLIFERATION IN THE FETUS, LEADING TO PULMONARY ARTERIAL REMODELING AND PULMONARY HYPERTENSION OF THE NEWBORN. THE MECHANISMS UNDERLYING THESE CONDITIONS REMAIN ENIGMATIC HOWEVER. WE HYPOTHESIZED THAT EPIGENETIC ALTERATIONS IN FETAL PASMC INDUCED BY HIGH-ALTITUDE LTH MAY PLAY AN IMPORTANT ROLE IN MODULATING THEIR PROLIFERATION DURING PULMONARY ARTERIAL REMODELING. TO TEST THIS HYPOTHESIS, WE HAVE ANALYZED EPIGENETIC ALTERATIONS IN THE PULMONARY VASCULATURE OF FETAL LAMBS EXPOSED TO HIGH-ALTITUDE LTH [PREGNANT EWES WERE KEPT AT 3,801 M ALTITUDE FROM ~40 TO 145 DAYS GESTATION] OR TO SEA LEVEL ATMOSPHERE. INTRAPULMONARY ARTERIES WERE ISOLATED, AND FETAL PASMC WERE CULTURED FROM BOTH CONTROL AND LTH FETUSES. COMPARED WITH CONTROLS, IN LTH FETUS PULMONARY ARTERIES MEASUREMENTS OF HISTONE ACETYLATION AND GLOBAL DNA METHYLATION DEMONSTRATED REDUCED LEVELS OF GLOBAL HISTONE 4 ACETYLATION AND DNA METHYLATION, ACCOMPANIED BY THE LOSS OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P21. TREATMENT OF LTH FETAL PASMCS WITH HISTONE DEACETYLASE (HDAC) INHIBITOR TRICHOSTATIN A DECREASED THEIR PROLIFERATION RATE, IN PART BECAUSE OF ALTERED EXPRESSION OF P21 AT BOTH RNA AND PROTEIN LEVEL. IN PASMC OF LTH FETUSES, HDAC INHIBITION ALSO DECREASED PDGF-INDUCED CELL MIGRATION AND ERK1/2 ACTIVATION AND MODULATED GLOBAL DNA METHYLATION. ON THE BASIS OF THESE OBSERVATIONS, WE PROPOSE THAT EPIGENETIC ALTERATIONS (REDUCED HISTONE ACETYLATION AND DNA METHYLATION) CAUSED BY CHRONIC HYPOXIA LEADS TO FETAL PASMC PROLIFERATION AND VESSEL REMODELING ASSOCIATED WITH VASCULAR PROLIFERATIVE DISEASE AND THAT THIS PROCESS IS REGULATED BY P21. 2012 8 2023 30 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 9 4197 25 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 10 3469 34 HYPOXIA-INDUCIBLE HISTONE LYSINE DEMETHYLASES: IMPACT ON THE AGING PROCESS AND AGE-RELATED DISEASES. HYPOXIA IS AN ENVIRONMENTAL STRESS AT HIGH ALTITUDE AND UNDERGROUND CONDITIONS BUT IT IS ALSO PRESENT IN MANY CHRONIC AGE-RELATED DISEASES, WHERE BLOOD FLOW INTO TISSUES IS IMPAIRED. THE OXYGEN-SENSING SYSTEM STIMULATES GENE EXPRESSION PROTECTING TISSUES AGAINST HYPOXIC INSULTS. HYPOXIA STABILIZES THE EXPRESSION OF HYPOXIA-INDUCIBLE TRANSCRIPTION FACTOR-1ALPHA (HIF-1ALPHA), WHICH CONTROLS THE EXPRESSION OF HUNDREDS OF SURVIVAL GENES RELATED TO E.G. ENHANCED ENERGY METABOLISM AND AUTOPHAGY. MOREOVER, MANY STRESS-RELATED SIGNALING MECHANISMS, SUCH AS OXIDATIVE STRESS AND ENERGY METABOLIC DISTURBANCES, AS WELL AS THE SIGNALING CASCADES VIA CERAMIDE, MTOR, NF-KAPPAB, AND TGF-BETA PATHWAYS, CAN ALSO INDUCE THE EXPRESSION OF HIF-1ALPHA PROTEIN TO FACILITATE CELL SURVIVAL IN NORMOXIA. HYPOXIA IS LINKED TO PROMINENT EPIGENETIC CHANGES IN CHROMATIN LANDSCAPE. SCREENING STUDIES HAVE INDICATED THAT THE STABILIZATION OF HIF-1ALPHA INCREASES THE EXPRESSION OF DISTINCT HISTONE LYSINE DEMETHYLASES (KDM). HIF-1ALPHA STIMULATES THE EXPRESSION OF KDM3A, KDM4B, KDM4C, AND KDM6B, WHICH ENHANCE GENE TRANSCRIPTION BY DEMETHYLATING H3K9 AND H3K27 SITES (REPRESSIVE EPIGENETIC MARKS). IN ADDITION, HIF-1ALPHA INDUCES THE EXPRESSION OF KDM2B AND KDM5B, WHICH REPRESS TRANSCRIPTION BY DEMETHYLATING H3K4ME2,3 SITES (ACTIVATING MARKS). HYPOXIA-INDUCIBLE KDMS SUPPORT LOCALLY THE GENE TRANSCRIPTION INDUCED BY HIF-1ALPHA, ALTHOUGH THEY CAN ALSO CONTROL GENOME-WIDE CHROMATIN LANDSCAPE, ESPECIALLY KDMS WHICH DEMETHYLATE H3K9 AND H3K27 SITES. THESE EPIGENETIC MARKS HAVE IMPORTANT ROLE IN THE CONTROL OF HETEROCHROMATIN SEGMENTS AND 3D FOLDING OF CHROMOSOMES, AS WELL AS THE GENETIC LOCI REGULATING CELL TYPE COMMITMENT, PROLIFERATION, AND CELLULAR SENESCENCE, E.G. THE INK4 BOX. A CHRONIC STIMULATION OF HIF-1ALPHA CAN PROVOKE TISSUE FIBROSIS AND CELLULAR SENESCENCE, WHICH BOTH ARE INCREASINGLY PRESENT WITH AGING AND AGE-RELATED DISEASES. WE WILL REVIEW THE REGULATION OF HIF-1ALPHA-DEPENDENT INDUCTION OF KDMS AND CLARIFY THEIR ROLE IN PATHOLOGICAL PROCESSES EMPHASIZING THAT LONG-TERM STRESS-RELATED INSULTS CAN IMPAIR THE MAINTENANCE OF CHROMATIN LANDSCAPE AND PROVOKE CELLULAR SENESCENCE AND TISSUE FIBROSIS ASSOCIATED WITH AGING AND AGE-RELATED DISEASES. 2016 11 4894 33 OXIDATIVE STRESS CAUSED BY ACUTE AND CHRONIC EXPOSITION TO ALTITUDE. IN THIS ARTICLE, CURRENT VIEWS ON CELLULAR AND MOLECULAR BIOLOGY (BIOCHEMICAL) MECHANISMS ARE DISCUSSED UNDER THE ASPECT OF ALTITUDE EXPOSITION. THE ANDEAN, TIBETAN, AND ETHIOPIAN PATTERNS OF ADAPTATION TO HIGH-ALTITUDE HYPOXIA ARE KNOWN [BEAL ET AL. (2002) PROC NATL ACAD SCI USA 99: 17215-17218]. THE PHYLOGENETIC TREE OF THE HUMAN SPECIES SUGGESTS THAT THERE ARE GENETIC DIFFERENCES IN ADAPTATION PATTERNS TO CHRONIC HYPOXIC HYPOXIA. FIVE DEFENSE MECHANISMS ARE WELL ESTABLISHED FOR LOWLANDERS WHO ARE EXPOSED TO ACUTE HYPOXIC HYPOXIA. CONSEQUENCES OF THE CELLULAR DECREASE IN ATP ARE THE FORMATION OF HYPOXANTHINE AND XANTHINE, WHICH ARE THE SUBSTRATES FOR THE MASSIVE FORMATION OF SUPEROXIDE ANION RADICALS AND HYDROGEN PEROXIDE VIA THE OXIDASE ACTIVITY OF THE XANTHINE OXIDOREDUCTASE REACTION. UNDER SEVERE HYPOXIA, ABOUT 51 % OF THE TOTAL INHALED OXYGEN IS USED TO FORM SUPEROXIDE ANION RADICALS IN RAT LIVER [GERBER ET AL. (1989) ADV EXP MED BIOL 253B, PLENUM PRESS, NEW YORK, 497-504]. THE REACTIVITY AND SELECTIVITY OF THE SUPEROXIDE ANION RADICAL ARE MODIFIED BY SPECIFIC INTERACTIONS AND ELECTRON EXCHANGE. IT IS COMMONLY ACCEPTED THAT THE SUPEROXIDE ANION RADICAL IN AQUEOUS SOLUTIONS HAS A LIFETIME IN THE MILLISECOND RANGE. HOWEVER, ELECTRON SPIN RESONANCE SPECTROSCOPY STUDIES IN A KO2/H2O/IRON ION SYSTEM REVEALED FOR THE FIRST TIME A STABILIZATION OF A PART OF THE INITIALLY ADDED SUPEROXIDE ANION RADICALS LASTING UP TO HOURS AT ROOM TEMPERATURE [FOLDES-PAPP (1992) GEN PHYSIOL BIOPHYS 11: 3-38]. SUPEROXIDE ANION RADICALS ADSORBED ON AN OXIDIC IRON HYDRATE PHASE IN AQUEOUS SYSTEMS MIGHT FUNCTION AS A STRONG OXIDANT SIMILAR TO THAT SPECIES WHICH HAS BEEN SUGGESTED TO BE A COMPLEX BETWEEN OXYGEN AND DIFFERENT VALENCE STATES OF IRON IN THE INITIATION OF LIPID PEROXIDATION BY FERROUS IRON. THERE WERE SERIOUS DOUBTS ABOUT THE IDENTITY OF ALKOXY RADICALS. FOR THE FIRST TIME, ALKOXY RADICALS WERE DIRECTLY DEMONSTRATED IN SOLUTION BY ELECTRON SPIN RESONANCE SPECTROSCOPY [FOLDES-PAPP ET AL. (1991) ADV SYNTH CATAL 333: 293-301]. THE REDOX STATUS IN MAMMALIAN CELLS IS MAINLY DETERMINED BY THE ANTIOXIDANT GLUTATHIONE, WHICH IS A KEY PLAYER IN MAINTAINING THE INTRACELLULAR REDOX EQUILIBRIUM AND IN THE METABOLIC REGULATION OF THE CELLULAR DEFENSE AGAINST OXIDATIVE STRESS. AS REACTIVE OXYGEN SPECIES OCCUPY AN ESSENTIAL ROLE IN MEMBRANE DAMAGE, THE IDEA OF MEMBRANE-BOUND ENZYMATIC DEFENSE MECHANISMS GETS A NEW DIMENSION [FOLDES-PAPP ET AL. (1981) ACTA BIOL MED GER 40: 1129-1132; FOLDES-PAPP AND MARETZKI (1982) ACTA BIOL MED GER 41: 1003-1008]. THE STEADY-STATE BETWEEN ANTIOXIDANTS AND PRO-OXIDANTS AFFECTS THE GENE EXPRESSION VIA HYPOXIA-INDUCED TRANSCRIPTION ACTIVITIES. THE TRANSCRIPTION FACTOR HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1) IS A GLOBAL REGULATOR OF OXYGEN HOMEOSTASIS. AS DISCUSSED IN THIS ARTICLE, HYPOXIA OR 'OXIDATIVE STRESS' IS ACCOMPANIED BY APPROPRIATE MOLECULAR ADAPTATION MECHANISMS AT THE ENZYMATIC OR EPIGENETIC LEVEL (ENZYMATIC AND NON-ENZYMATIC RADICAL INHIBITORS, POSTTRANSLATIONAL MODIFICATIONS) AND AT THE GENETIC LEVEL (TRANSCRIPTION, TRANSLATION). 2005 12 5420 26 REGULATION OF HYPOXIA-INDUCIBLE FACTOR IN KIDNEY DISEASE. HYPOXIA PLAYS A CRUCIAL ROLE IN THE PATHOPHYSIOLOGY OF ACUTE KIDNEY INJURY (AKI) AND PRESUMABLY ALSO CHRONIC KIDNEY DISEASE (CKD). HYPOXIA-INDUCIBLE FACTOR (HIF) IS THE MASTER TRANSCRIPTION FACTOR THAT REGULATES ADAPTIVE RESPONSES AGAINST HYPOXIA. UNDER HYPOXIC CONDITIONS, HIF ACTIVATES TARGET GENES WITH HYPOXIA-RESPONSIVE ELEMENTS IN THEIR REGULATORY REGIONS. THE HIF ISOFORMS AND REGULATORS OF HIF (I.E. PROLYL HYDROXYLASES) SHOW CELL TYPE-SPECIFIC DISTRIBUTIONS. HYPOXIA IS OBSERVED IN BOTH ISCHAEMIC AND SO-CALLED NON-ISCHAEMIC FORMS OF AKI. IN ADDITION TO THE ACUTE PHASE, HYPOXIA MAY ENSUE DURING THE RECOVERY PHASE OF AKI, POSSIBLY DUE TO THE OXYGEN-CONSUMING PROCESSES OF CELL GROWTH AND PROLIFERATION FOR REPAIR. ALTHOUGH HIF PROTECTS THE KIDNEY AGAINST AKI, INTRINSIC HIF ACTIVATION IS SUBMAXIMAL IN AKI AND FURTHER AUGMENTATION OF HIF AMELIORATES DISEASE MANIFESTATIONS. THE KIDNEY IN CKD ALSO SUFFERS FROM HYPOXIA CAUSED BY MULTIPLE MECHANISMS, INCLUDING SUSTAINED OXYGEN DEMANDS IN THE REMAINING NEPHRONS DUE TO MALADAPTIVE TUBULOGLOMERULAR FEEDBACK. WHETHER HIF IS CHRONICALLY UPREGULATED IN CKD IS CONTENTIOUS. HYPOXIA-INDUCIBLE FACTOR ACTIVATION IS A PROMISING THERAPEUTIC APPROACH TO CKD, BUT EXCESSIVE ACTIVATION OF HIF MAY BE DELETERIOUS. IT IS LIKELY THAT THERE IS A THERAPEUTIC WINDOW OF HIF ACTIVATION IN CHRONIC CONDITIONS. UNDER CERTAIN CIRCUMSTANCES, ANIMALS WITH CKD ARE PROTECTED AGAINST AKI AND THIS MAY BE EXPLAINED BY NON-PHYSIOLOGICAL HYPOXIA OF THE KIDNEY AND SUBSEQUENT HIF EXPRESSION. IN ADDITION, AN ACUTE HYPOXIC INSULT MAY INDUCE LONG-LASTING CHANGES, POSSIBLY INCLUDING EPIGENETIC MODIFICATIONS INDUCED BY HIF. THESE OBSERVATIONS SUGGEST A COMPLEX INTERACTION BETWEEN AKI AND CKD VIA HYPOXIA AND HIF ACTIVATION. 2013 13 2362 22 EPIGENETIC REGULATION OF SNAP25 PREVENTS PROGRESSIVE GLUTAMATE EXCITOTOXICTY IN HYPOXIC CA3 NEURONS. EXPOSURE TO GLOBAL HYPOXIA AND ISCHEMIA HAS BEEN REPORTED TO CAUSE NEURODEGENERATION IN THE HIPPOCAMPUS WITH CA3 NEURONS. THIS NEURONAL DAMAGE IS PROGRESSIVE DURING THE INITIAL PHASE OF EXPOSURE BUT MAINTAINS A PLATEAU ON PROLONGED EXPOSURE. THE PRESENT STUDY ON SPRAGUE DAWLEY RATS AIMED AT UNDERSTANDING THE UNDERLYING MOLECULAR AND EPIGENETIC MECHANISMS THAT LEAD TO HYPOXIC ADAPTATION OF CA3 NEURONS ON PROLONGED EXPOSURE TO A GLOBAL HYPOXIA. OUR RESULTS SHOW STAGNANCY IN NEURODEGENERATION IN CA3 REGION BEYOND 14 DAYS OF CHRONIC EXPOSURE TO HYPOBARIA SIMULATING AN ALTITUDE OF 25,000 FT. DESPITE INCREASED SYNAPTOSOMAL GLUTAMATE AND HIGHER EXPRESSION OF NR1 SUBUNIT OF NMDA RECEPTORS, WE OBSERVED DECREASE IN POST-SYNAPTIC DENSITY AND ACCUMULATION OF SYNAPTIC VESICLES AT THE PRE-SYNAPTIC TERMINALS. MOLECULAR INVESTIGATIONS INVOLVING WESTERN BLOT AND REAL-TIME PCR SHOWED DURATION-DEPENDENT DECREASE IN THE EXPRESSION OF SNAP-25 RESULTING IN REDUCED VESICULAR DOCKING AND SYNAPTIC REMODELING. CHIP ASSAYS FOR EPIGENETIC FACTORS SHOWED DECREASED EXPRESSION OF H3K9AC AND H3K14AC RESULTING IN SNAP-25 PROMOTER SILENCING DURING PROLONGED HYPOXIA. ADMINISTRATION OF SODIUM BUTYRATE, A NON-SPECIFIC HDAC INHIBITOR, DURING 21 DAYS HYPOXIC EXPOSURE PREVENTED SNAP-25 DOWNREGULATION BUT INCREASED CA3 NEURODEGENERATION. THIS EPIGENETIC REGULATION OF SNAP-25 PROMOTER WAS INDEPENDENT OF INCREASED DNMT3B EXPRESSION AND PROMOTER METHYLATION. OUR FINDINGS PROVIDE A NOVEL INSIGHT INTO EPIGENETIC FACTORS-MEDIATED SYNAPTIC REMODELING TO PREVENT EXCITOTOXIC NEURODEGENERATION ON PROLONGED EXPOSURE TO GLOBAL HYPOBARIC HYPOXIA. 2017 14 4138 34 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 15 4813 22 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 16 443 29 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 17 2614 31 EPIGENETICS: NEW QUESTIONS ON THE RESPONSE TO HYPOXIA. REDUCTION IN OXYGEN LEVELS BELOW NORMAL CONCENTRATIONS PLAYS IMPORTANT ROLES IN DIFFERENT NORMAL AND PATHOLOGICAL CONDITIONS, SUCH AS DEVELOPMENT, TUMORIGENESIS, CHRONIC KIDNEY DISEASE AND STROKE. ORGANISMS EXPOSED TO HYPOXIA TRIGGER CHANGES AT BOTH CELLULAR AND SYSTEMIC LEVELS TO RECOVER OXYGEN HOMEOSTASIS. MOST OF THESE PROCESSES ARE MEDIATED BY HYPOXIA INDUCIBLE FACTORS, HIFS, A FAMILY OF TRANSCRIPTION FACTORS THAT DIRECTLY INDUCE THE EXPRESSION OF SEVERAL HUNDRED GENES IN MAMMALIAN CELLS. ALTHOUGH DIFFERENT ASPECTS OF HIF REGULATION ARE WELL KNOWN, IT IS STILL UNCLEAR BY WHICH PRECISE MECHANISM HIFS ACTIVATE TRANSCRIPTION OF THEIR TARGET GENES. CONCOMITANTLY, HYPOXIA PROVOKES A DRAMATIC DECREASE OF GENERAL TRANSCRIPTION THAT SEEMS TO RELY IN PART ON EPIGENETIC CHANGES THROUGH A POORLY UNDERSTOOD MECHANISM. IN THIS REVIEW WE DISCUSS THE CURRENT KNOWLEDGE ON CHROMATIN CHANGES INVOLVED IN HIF DEPENDENT GENE ACTIVATION, AS WELL AS ON OTHER EPIGENETIC CHANGES, NOT NECESSARILY LINKED TO HIF THAT TAKE PLACE UNDER HYPOXIC CONDITIONS. 2011 18 3466 20 HYPOXIA AS A KEY PLAYER IN THE AKI-TO-CKD TRANSITION. RECENT CLINICAL AND ANIMAL STUDIES HAVE SHOWN THAT ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY COMPLETE RECOVERY OF RENAL FUNCTION, CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD). RENAL HYPOXIA IS EMERGING AS A KEY PLAYER IN THE PATHOPHYSIOLOGY OF THE AKI-TO-CKD TRANSITION. CAPILLARY RAREFACTION AFTER AKI EPISODES INDUCES RENAL HYPOXIA, WHICH CAN IN TURN PROFOUNDLY AFFECT TUBULAR EPITHELIAL CELLS, (MYO)FIBROBLASTS, AND INFLAMMATORY CELLS, CULMINATING IN TUBULOINTERSTITIAL FIBROSIS, I.E., PROGRESSION TO CKD. DAMAGED TUBULAR EPITHELIAL CELLS THAT FAIL TO REDIFFERENTIATE MIGHT SUPPLY A DECREASED AMOUNT OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND CONTRIBUTE TO CAPILLARY RAREFACTION, THUS AGGRAVATING HYPOXIA AND FORMING A VICIOUS CYCLE. MOUNTING EVIDENCE ALSO SHOWS THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO RENAL HYPOXIA IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION. ANIMAL EXPERIMENTS SUGGEST THAT TARGETING HYPOXIA IS A PROMISING STRATEGY TO BLOCK THE TRANSITION FROM AKI TO CKD. HOWEVER, THE PRECISE MECHANISMS BY WHICH HYPOXIA INDUCES THE AKI-TO-CKD TRANSITION AND BY WHICH HYPOXIA-INDUCIBLE FACTOR ACTIVATION CAN EXERT A PROTECTIVE EFFECT IN THIS CONTEXT SHOULD BE CLARIFIED IN FURTHER STUDIES. 2014 19 3633 26 INCREASE IN HDAC9 SUPPRESSES MYOBLAST DIFFERENTIATION VIA EPIGENETIC REGULATION OF AUTOPHAGY IN HYPOXIA. EXTREMELY REDUCED OXYGEN (O(2)) LEVELS ARE DETRIMENTAL TO MYOGENIC DIFFERENTIATION AND MULTINUCLEATED MYOTUBE FORMATION, AND CHRONIC EXPOSURE TO HIGH-ALTITUDE HYPOXIA HAS BEEN REPORTED TO BE AN IMPORTANT FACTOR IN SKELETAL MUSCLE ATROPHY. HOWEVER, HOW CHRONIC HYPOXIA CAUSES MUSCLE DYSFUNCTION REMAINS UNKNOWN. IN THE PRESENT STUDY, WE FOUND THAT SEVERE HYPOXIA (1% O(2)) SIGNIFICANTLY INHIBITED THE FUNCTION OF C2C12 CELLS (FROM A MYOBLAST CELL LINE). IMPORTANTLY, THE IMPAIRMENT WAS CONTINUOUSLY MANIFESTED EVEN DURING CULTURE UNDER NORMOXIC CONDITIONS FOR SEVERAL PASSAGES. MECHANISTICALLY, WE REVEALED THAT HISTONE DEACETYLASES 9 (HDAC9), A MEMBER OF THE HISTONE DEACETYLASE FAMILY, WAS SIGNIFICANTLY INCREASED IN C2C12 CELLS UNDER HYPOXIC CONDITIONS, THEREBY INHIBITING INTRACELLULAR AUTOPHAGY LEVELS BY DIRECTLY BINDING TO THE PROMOTER REGIONS OF ATG7, BECLIN1, AND LC3. THIS PHENOMENON RESULTED IN THE SEQUENTIAL DEPHOSPHORYLATION OF GSK3BETA AND INACTIVATION OF THE CANONICAL WNT PATHWAY, IMPAIRING THE FUNCTION OF THE C2C12 CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT HYPOXIA-INDUCED MYOBLAST DYSFUNCTION IS DUE TO ABERRANT EPIGENETIC REGULATION OF AUTOPHAGY, AND OUR EXPERIMENTAL EVIDENCE REVEALS THE POSSIBLE MOLECULAR PATHOGENESIS RESPONSIBLE FOR SOME MUSCLE DISEASES CAUSED BY CHRONIC HYPOXIA AND SUGGESTS A POTENTIAL THERAPEUTIC OPTION. 2019 20 3467 22 HYPOXIA, HIF, AND ASSOCIATED SIGNALING NETWORKS IN CHRONIC KIDNEY DISEASE. THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE (CKD) IS COMPLEX AND APPARENTLY MULTIFACTORIAL. HYPOXIA OR DECREASE IN OXYGEN SUPPLY IN KIDNEY TISSUES HAS BEEN IMPLICATED IN CKD. HYPOXIA INDUCIBLE FACTORS (HIF) ARE A SMALL FAMILY OF TRANSCRIPTION FACTORS THAT ARE MAINLY RESPONSIVE TO HYPOXIA AND MEDIATE HYPOXIC RESPONSE. HIF PLAYS A CRITICAL ROLE IN RENAL FIBROSIS DURING CKD THROUGH THE MODULATION OF GENE TRANSCRIPTION, CROSSTALK WITH MULTIPLE SIGNALING PATHWAYS, EPITHELIAL-MESENCHYMAL TRANSITION, AND EPIGENETIC REGULATION. MOREOVER, HIF ALSO CONTRIBUTES TO THE DEVELOPMENT OF VARIOUS PATHOLOGICAL CONDITIONS ASSOCIATED WITH CKD, SUCH AS ANEMIA, INFLAMMATION, ABERRANT ANGIOGENESIS, AND VASCULAR CALCIFICATION. TREATMENTS TARGETING HIF AND RELATED SIGNALING PATHWAYS FOR CKD THERAPY ARE BEING DEVELOPED WITH PROMISING CLINICAL BENEFITS, ESPECIALLY FOR ANEMIA. THIS REVIEW PRESENTS AN UPDATED ANALYSIS OF HYPOXIA RESPONSE, HIF, AND THEIR ASSOCIATED SIGNALING NETWORK INVOLVED IN THE PATHOGENESIS OF CKD. 2017