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Circulation Research Jun 2023Atrial fibrillation (AF), the most common arrhythmia, is associated with the downregulation of (encoding FKBP5 [FK506 binding protein 5]). However, the function of...
BACKGROUND
Atrial fibrillation (AF), the most common arrhythmia, is associated with the downregulation of (encoding FKBP5 [FK506 binding protein 5]). However, the function of FKBP5 in the heart remains unknown. Here, we elucidate the consequences of cardiomyocyte-restricted loss of FKBP5 on cardiac function and AF development and study the underlying mechanisms.
METHODS
Right atrial samples from patients with AF were used to assess the protein levels of FKBP5. A cardiomyocyte-specific FKBP5 knockdown mouse model was established by crossbreeding mice with mice. Cardiac function and AF inducibility were assessed by echocardiography and programmed intracardiac stimulation. Histology, optical mapping, cellular electrophysiology, and biochemistry were employed to elucidate the proarrhythmic mechanisms due to loss of cardiomyocyte FKBP5.
RESULTS
FKBP5 protein levels were lower in the atrial lysates of patients with paroxysmal AF or long-lasting persistent (chronic) AF. Cardiomyocyte-specific knockdown mice exhibited increased AF inducibility and duration compared with control mice. Enhanced AF susceptibility in cardiomyocyte-specific knockdown mice was associated with the development of action potential alternans and spontaneous Ca waves, and increased protein levels and activity of the NCX1 (Na/Ca-exchanger 1), mimicking the cellular phenotype of chronic AF patients. FKBP5-deficiency enhanced transcription of (encoding NCX1) via transcription factor hypoxia-inducible factor 1α. In vitro studies revealed that FKBP5 negatively modulated the protein levels of hypoxia-inducible factor 1α by competitively interacting with heat-shock protein 90. Injections of the heat-shock protein 90 inhibitor 17-AAG normalized protein levels of hypoxia-inducible factor 1α and NCX1 and reduced AF susceptibility in cardiomyocyte-specific knockdown mice. Furthermore, the atrial cardiomyocyte-selective knockdown of FKBP5 was sufficient to enhance AF arrhythmogenesis.
CONCLUSIONS
This is the first study to demonstrate a role for the FKBP5-deficiency in atrial arrhythmogenesis and to establish FKBP5 as a negative regulator of hypoxia-inducible factor 1α in cardiomyocytes. Our results identify a potential molecular mechanism for the proarrhythmic NCX1 upregulation in chronic AF patients.
Topics: Mice; Animals; Atrial Fibrillation; Down-Regulation; Myocytes, Cardiac; Hypoxia; Heat-Shock Proteins
PubMed: 37154033
DOI: 10.1161/CIRCRESAHA.122.322213 -
Signal Transduction and Targeted Therapy Nov 2023Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in... (Review)
Review
Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases. From the research history and milestone events related to hypoxia in cardiovascular development and diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal and spatial perspectives, encompassing the occurrence and progression of hypoxia (gradual decline in oxygen concentration), the acute and chronic manifestations of hypoxia, and the geographical characteristics of hypoxia (natural selection at high altitudes). Furthermore, hypoxia signaling pathways are associated with natural rhythms, such as diurnal and hibernation processes. In addition to innate factors and natural selection, it has been found that epigenetics, as a postnatal factor, profoundly influences the hypoxic response and progression within the cardiovascular system. Within this intricate process, interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established. Thus, it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more therapeutic targets and make reasonable advancements in clinical research, including FDA-approved drugs and ongoing clinical trials, to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases.
Topics: Humans; Cardiovascular Diseases; Cardiovascular System; Hypoxia; Oxygen; Epigenesis, Genetic
PubMed: 37981648
DOI: 10.1038/s41392-023-01652-9 -
Ugeskrift For Laeger Dec 2023Home oxygen therapy is an acknowledged treatment for patients suffering from chronic hypoxaemia, due to pulmonary or cardiac disease, and may have positive effects on... (Review)
Review
Home oxygen therapy is an acknowledged treatment for patients suffering from chronic hypoxaemia, due to pulmonary or cardiac disease, and may have positive effects on survival and quality of life. The risks and side effects of the treatment are usually mild, and the equipment has developed to become relatively affordable, accessible and easy to transport. Adjustments in the oxygen settings can be necessary when travelling by airplane or during physical effort or sleep. Prescription and follow-ups are usually best maintained by hospital departments with expertise in pulmonary medicine, as argued in this review.
Topics: Humans; Quality of Life; Oxygen Inhalation Therapy; Lung; Oxygen; Denmark; Hypoxia
PubMed: 38078470
DOI: No ID Found -
Cell Death & Disease Jul 2023Perturbations of mitochondrial proteostasis have been associated with aging, neurodegenerative diseases, and recently with hypoxic injury. While examining...
Perturbations of mitochondrial proteostasis have been associated with aging, neurodegenerative diseases, and recently with hypoxic injury. While examining hypoxia-induced mitochondrial protein aggregation in C. elegans, we found that sublethal hypoxia, sodium azide, or heat shock-induced abundant ethidium bromide staining mitochondrial granules that preceded evidence of protein aggregation. Genetic manipulations that reduce cellular and organismal hypoxic death block the formation of these mitochondrial stress granules (mitoSG). Knockdown of mitochondrial nucleoid proteins also blocked the formation of mitoSG by a mechanism distinct from the mitochondrial unfolded protein response. Lack of the major mitochondrial matrix protease LONP-1 resulted in the constitutive formation of mitoSG without external stress. Ethidium bromide-staining RNA-containing mitochondrial granules were also observed in rat cardiomyocytes treated with sodium azide, a hypoxia mimetic. Mitochondrial stress granules are an early mitochondrial pathology controlled by LONP and the nucleoid, preceding hypoxia-induced protein aggregation.
Topics: Animals; Rats; Caenorhabditis elegans; Protein Aggregates; Ethidium; Sodium Azide; Stress Granules; Hypoxia; Mitochondrial Proteins
PubMed: 37468471
DOI: 10.1038/s41419-023-05988-6 -
Cell Feb 2024The electron transport chain (ETC) of mitochondria, bacteria, and archaea couples electron flow to proton pumping and is adapted to diverse oxygen environments....
The electron transport chain (ETC) of mitochondria, bacteria, and archaea couples electron flow to proton pumping and is adapted to diverse oxygen environments. Remarkably, in mice, neurological disease due to ETC complex I dysfunction is rescued by hypoxia through unknown mechanisms. Here, we show that hypoxia rescue and hyperoxia sensitivity of complex I deficiency are evolutionarily conserved to C. elegans and are specific to mutants that compromise the electron-conducting matrix arm. We show that hypoxia rescue does not involve the hypoxia-inducible factor pathway or attenuation of reactive oxygen species. To discover the mechanism, we use C. elegans genetic screens to identify suppressor mutations in the complex I accessory subunit NDUFA6/nuo-3 that phenocopy hypoxia rescue. We show that NDUFA6/nuo-3(G60D) or hypoxia directly restores complex I forward activity, with downstream rescue of ETC flux and, in some cases, complex I levels. Additional screens identify residues within the ubiquinone binding pocket as being required for the rescue by NDUFA6/nuo-3(G60D) or hypoxia. This reveals oxygen-sensitive coupling between an accessory subunit and the quinone binding pocket of complex I that can restore forward activity in the same manner as hypoxia.
Topics: Animals; Mice; Caenorhabditis elegans; Electron Transport Complex I; Hypoxia; Mitochondria; Oxygen
PubMed: 38215760
DOI: 10.1016/j.cell.2023.12.010 -
The Journal of Clinical Investigation Feb 2024Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in the...
Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in the development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health, and the small GTPase RAB7 regulates many functions of this system. Here, we explored the role of RAB7 in endothelial cell (EC) function and lung vascular homeostasis. We found reduced expression of RAB7 in ECs from patients with PAH. Endothelial haploinsufficiency of RAB7 caused spontaneous pulmonary hypertension (PH) in mice. Silencing of RAB7 in ECs induced broad changes in gene expression revealed via RNA-Seq, and RAB7-silenced ECs showed impaired angiogenesis and expansion of a senescent cell fraction, combined with impaired endolysosomal trafficking and degradation, suggesting inhibition of autophagy at the predegradation level. Furthermore, mitochondrial membrane potential and oxidative phosphorylation were decreased, and glycolysis was enhanced. Treatment with the RAB7 activator ML-098 reduced established PH in rats with chronic hypoxia/SU5416. In conclusion, we demonstrate for the first time to our knowledge the fundamental impairment of EC function by loss of RAB7, causing PH, and show RAB7 activation to be a potential therapeutic strategy in a preclinical model of PH.
Topics: Animals; Humans; Mice; Rats; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Hypoxia; Lung; Pulmonary Artery
PubMed: 38015641
DOI: 10.1172/JCI169441 -
Seminars in Cancer Biology Dec 2023Disruption of oxygen homeostasis, resulting from an imbalance between O supply and demand during malignant proliferation, leads to the development of hypoxic tumor... (Review)
Review
Disruption of oxygen homeostasis, resulting from an imbalance between O supply and demand during malignant proliferation, leads to the development of hypoxic tumor microenvironments that promote the acquisition of aggressive cancer cell phenotypes linked to metastasis and patient mortality. In this review, the mechanistic links between tumor hypoxia and metastatic progression are presented. Current status and perspectives of targeting hypoxia signaling pathways as a strategy to halt cancer cell metastatic activities are emphasized.
Topics: Humans; Hypoxia; Tumor Hypoxia; Cell Hypoxia
PubMed: 37926346
DOI: 10.1016/j.semcancer.2023.11.001 -
Nigerian Journal of Clinical Practice Nov 2023The physical examination is a key part of a continuum that extends from the history of the present illness to the therapeutic outcome. An understanding of the... (Review)
Review
The physical examination is a key part of a continuum that extends from the history of the present illness to the therapeutic outcome. An understanding of the pathophysiological mechanism behind a physical sign is essential for arriving at the correct diagnosis. Early detection of deteriorating physical/vital signs and their appropriate interpretation is thus the key to achieve correct and timely management. By definition, vital signs are "the signs of life that may be monitored or measured, namely pulse rate, respiratory rate, body temperature, and blood pressure." Vital signs are the simplest, cheapest and probably the most inexpensive information gathered bedside in outpatient or hospitalized patients. The pulse oximeter was introduced in the 1980s. It is an accurate and non-invasive method for the measurement of arterial hemoglobin oxygen saturation (SaO2). Pulse oximetry-based arterial oxygen saturation can be effectively used bedside in in-hospital and ambulatory patients with diagnosed or suspected lung disease. The present pandemic of COVID-19 should be considered as a wake-up call. Articles related to arterial oxygen saturation and its importance as a vital sign in patient care were searched online especially in PubMed. Available studies were studied in full length and data was extracted. Discussion: A. Clinical Utility of Oxygen Saturation Monitoring: There are many studies reporting the clinical applicability and usefulness of pulse oximetry in the early detection of hypoxemic events during intraoperative and postoperative periods. B. Role of clinical expertise accompanied by knowledge of physiology: A diagnostic sign is useful only if it is interpreted accurately and applied appropriately while evaluating a patient. The World Health Organisation also appreciates these facts and published "The WHO Pulse Oximetry Training Manual." Understanding the physiology behind and overcoming limitations of the diagnostic sign by clinical expertise is important. While using pulse oximetry, a clinician needs to keep in mind the sigmoidal nature of the oxygen-Hb dissociation curve. Considering these benefits of SaO2 measurement, there have been several references in the past to consider oxygen saturation as the fifth vital sign. In the present pandemic oxygen saturation i.e., SpO2 (arterial oxygen saturation) measured by pulse oxymeter, has been the single most important warning and prognostic sign be it for households, offices, street vendors, hospitals or governments. Measurement of trends of SaO2 added with respiratory rate will provide clinicians with a holistic overview of respiratory functions and multidimensional conditions associated with hypoxemia.
Topics: Humans; Heart Rate; Hypoxia; Oximetry; Oxygen; Oxygen Saturation
PubMed: 38044759
DOI: 10.4103/njcp.njcp_2026_21 -
Biomolecules Dec 2023The malignancy of glioblastoma (GBM), the most aggressive type of human brain tumor, strongly correlates with the presence of hypoxic areas within the tumor mass. Oxygen... (Review)
Review
The malignancy of glioblastoma (GBM), the most aggressive type of human brain tumor, strongly correlates with the presence of hypoxic areas within the tumor mass. Oxygen levels have been shown to control several critical aspects of tumor aggressiveness, such as migration/invasion and cell death resistance, but the underlying mechanisms are still unclear. GBM cells express abundant K and Cl channels, whose activity supports cell volume and membrane potential changes, critical for cell proliferation, migration and death. Volume-regulated anion channels (VRAC), which mediate the swelling-activated Cl current, and the large-conductance Ca-activated K channels (BK) are both functionally upregulated in GBM cells, where they control different aspects underlying GBM malignancy/aggressiveness. The functional expression/activity of both VRAC and BK channels are under the control of the oxygen levels, and these regulations are involved in the hypoxia-induced GBM cell aggressiveness. The present review will provide a comprehensive overview of the literature supporting the role of these two channels in the hypoxia-mediated GBM malignancy, suggesting them as potential therapeutic targets in the treatment of GBM.
Topics: Humans; Glioblastoma; Large-Conductance Calcium-Activated Potassium Channels; Cell Line, Tumor; Hypoxia; Oxygen
PubMed: 38136613
DOI: 10.3390/biom13121742 -
Identification and analysis of key hypoxia- and immune-related genes in hypertrophic cardiomyopathy.Biological Research Aug 2023Hypertrophic cardiomyopathy (HCM), an autosomal dominant genetic disease, is the main cause of sudden death in adolescents and athletes globally. Hypoxia and immune...
BACKGROUND
Hypertrophic cardiomyopathy (HCM), an autosomal dominant genetic disease, is the main cause of sudden death in adolescents and athletes globally. Hypoxia and immune factors have been revealed to be related to the pathology of HCM. There is growing evidence of a role for hypoxia and inflammation as triggers and enhancers in the pathology in HCM. However, the role of hypoxia- and immune-related genes in HCM have not been reported.
METHODS
Firstly, we obtained four HCM-related datasets from the Gene Expression Omnibus (GEO) database for differential expression analysis. Immune cells significantly expressed in normal samples and HCM were then screened by a microenvironmental cell population counter (MCP-counter) algorithm. Next, hypoxia- and immune-related genes were screened by the LASSO + support vector machine recursive feature elimination (SVM-RFE) and weighted gene co-expression network analysis (WGCNA). Single-gene enrichment analysis and expression validation of key genes were then performed. Finally, we constructed a competing endogenous RNA (ceRNA) network of key genes.
RESULTS
In this study, 35 differentially expressed hypoxia genes were found. By using LASSO + SVM-RFE analysis, 10 more targets with differentially expressed hypoxia genes were identified. The MCP-count algorithm yielded five differentially expressed immune cells, and after assessing them for WGCNA characteristics, 612 immune genes were discovered. When hypoxia and immune genes were combined for cross-tabulation analysis, three hypoxia- and immune-related genes (ATP2A2, DDAH1, and OMA1) were identified.
CONCLUSION
Based on hypoxia characteristic genes, three key genes were identified. These were also significantly related to immune activation, which proves a theoretical basis and reference value for studying the relationship between HCM and hypoxia and immunity.
Topics: Adolescent; Humans; Hypoxia; Cardiomyopathy, Hypertrophic; Gene Expression Profiling; Inflammation
PubMed: 37559135
DOI: 10.1186/s40659-023-00451-4