bims-midhyp 2023-07-30 papers

bims-midhyp

Biomed News

on Mitochondrial dysfunction and hypoxia

Issue of 2023–07–30
seventeen papers selected by
Alia Ablieh, Universität Heidelberg

Searching for molecular hypoxia sensors among oxygen-dependent enzymes.
Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence.
Nonequilibrium thermodynamics and mitochondrial protein content predict insulin sensitivity and fuel selection during exercise in human skeletal muscle.
Matrix metalloproteinase-2 proteolyzes mitofusin-2 and impairs mitochondrial function during myocardial ischemia-reperfusion injury.
High-altitude cerebral hypoxia promotes mitochondrial dysfunction and apoptosis of mouse neurons.
RNA binding protein: coordinated expression between the nuclear and mitochondrial genomes in tumors.
SIRT5 alleviates liver ischemia/reperfusion injury by regulating mitochondrial succinylation and oxidative stress.
Hypoxia inducible factor-1α is an important regulator of macrophage biology.
Exploring the Role of NCX1 and NCX3 in an In Vitro Model of Metabolism Impairment: Potential Neuroprotective Targets for Alzheimer's Disease.
Metabolomic and Lipidomic Analysis of the Colorectal Adenocarcinoma Cell Line HT29 in Hypoxia and Reoxygenation.
The Role of ATP-Binding Cassette Proteins in Stem Cell Pluripotency.
Computational Analysis Reveals Unique Binding Patterns of Oxygenated and Deoxygenated Myoglobin to the Outer Mitochondrial Membrane.
Targeting Endothelial HIF2α/ARNT Expression for Ischemic Heart Disease Therapy.
Age-related pathophysiological alterations in molecular stress markers and key modulators of hypoxia.
Reduced Tie2 in Microvascular Endothelial Cells Is Associated with Organ-Specific Adhesion Molecule Expression in Murine Health and Endotoxemia.
The protective roles of citrus flavonoids, naringenin, and naringin on endothelial cell dysfunction in diseases.
Chronic Intermittent Hypoxia-Induced Diaphragm Muscle Weakness Is NADPH Oxidase-2 Dependent.

Elife. 2023 Jul 26. pii: e87705. [Epub ahead of print]12

Searching for molecular hypoxia sensors among oxygen-dependent enzymes.

Li Li, Susan Shen, Philip Bickler, Matthew P Jacobson, Lani F Wu, Steven J Altschuler.

  The ability to sense and respond to changes in cellular oxygen levels is critical for aerobic organisms and requires a molecular oxygen sensor. The prototypical sensor is the oxygen-dependent enzyme PHD: hypoxia inhibits its ability to hydroxylate the transcription factor HIF, causing HIF to accumulate and trigger the classic HIF-dependent hypoxia response. A small handful of other oxygen sensors are known, all of which are oxygen-dependent enzymes. However, hundreds of oxygen-dependent enzymes exist among aerobic organisms, raising the possibility that additional sensors remain to be discovered. This review summarizes known and potential hypoxia sensors among human O2-dependent enzymes and highlights their possible roles in hypoxia-related adaptation and diseases.

Keywords:  cell biology; hypoxia; hypoxia sensors; oxygen; oxygen-dependent enzymes

DOI:  https://doi.org/10.7554/eLife.87705
Biochim Biophys Acta Gene Regul Mech. 2023 Jul 25. pii: S1874-9399(23)00058-5. [Epub ahead of print] 194963

Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence.

Tamara Rosell-Garcia, Sergio Rivas-Muñoz, Koryu Kin, Verónica Romero-Albillo, Silvia Alcaraz, Carlos Fernandez-Tornero, Fernando Rodriguez-Pascual.

  Transcriptional activity of the hypoxia inducible factor (HIF) relies on the formation of a heterodimer composed of an oxygen-regulated α-subunit and a stably expressed β-subunit. Heterodimeric HIF activates expression by binding to RCGTG motifs within promoters of hypoxia-activated genes. Some hypoxia targets also possess an adjacent HIF ancillary sequence (HAS) reported to increase transcription but whose function remains obscure. Here, we investigate the contribution of the HAS element to the hypoxia response and its mechanism of action, using the HAS-containing prolyl 4-hydroxylase subunit α1 (P4HA1) as a gene model in NIH/3 T3 mouse embryonic fibroblasts and HEK293 human embryonic kidney cells. Our HIF overexpression experiments demonstrate that the HAS motif is essential for full induction by hypoxia and that the presence of the tandem HAS/HIF, as opposed to HIF-only sequences, provides HIF proteins with the capacity to form complexes of stoichiometry beyond the classical heterodimer, likely tetramers, to cooperatively potentiate hypoxia-induced transcription. We also provide evidence of the crucial role played by the Fα helix of the PAS-B domain of the HIF1β subunit to support the interaction between heterodimers. Functional analysis showed that human genes containing the HAS/HIF motifs are better responders to hypoxia, and their promoters are enriched for specific transcription factor binding sites. Gene ontology enrichment revealed a predominance of HAS/HIF in genes primarily related to tissue formation and development. Our findings add an extra level of regulation of the hypoxia/HIF signaling through multimerization of HIF proteins on regulatory elements containing the HAS/HIF motifs.

Keywords:  Cooperation; HIF ancillary sequence; HIF binding site; Hypoxia inducible factor; Hypoxia response

DOI:  https://doi.org/10.1016/j.bbagrm.2023.194963
Front Physiol. 2023 ;14 1208186

Nonequilibrium thermodynamics and mitochondrial protein content predict insulin sensitivity and fuel selection during exercise in human skeletal muscle.

Rocio Zapata Bustos, Dawn K Coletta, Jean-Philippe Galons, Lisa B Davidson, Paul R Langlais, Janet L Funk, Wayne T Willis, Lawrence J Mandarino.

  Introduction: Many investigators have attempted to define the molecular nature of changes responsible for insulin resistance in muscle, but a molecular approach may not consider the overall physiological context of muscle. Because the energetic state of ATP (ΔGATP) could affect the rate of insulin-stimulated, energy-consuming processes, the present study was undertaken to determine whether the thermodynamic state of skeletal muscle can partially explain insulin sensitivity and fuel selection independently of molecular changes. Methods: 31P-MRS was used with glucose clamps, exercise studies, muscle biopsies and proteomics to measure insulin sensitivity, thermodynamic variables, mitochondrial protein content, and aerobic capacity in 16 volunteers. Results: After showing calibrated 31P-MRS measurements conformed to a linear electrical circuit model of muscle nonequilibrium thermodynamics, we used these measurements in multiple stepwise regression against rates of insulin-stimulated glucose disposal and fuel oxidation. Multiple linear regression analyses showed 53% of the variance in insulin sensitivity was explained by 1) VO2max (p = 0.001) and the 2) slope of the relationship of ΔGATP with the rate of oxidative phosphorylation (p = 0.007). This slope represents conductance in the linear model (functional content of mitochondria). Mitochondrial protein content from proteomics was an independent predictor of fractional fat oxidation during mild exercise (R2 = 0.55, p = 0.001). Conclusion: Higher mitochondrial functional content is related to the ability of skeletal muscle to maintain a greater ΔGATP, which may lead to faster rates of insulin-stimulated processes. Mitochondrial protein content per se can explain fractional fat oxidation during mild exercise.

Keywords:  31 P-magnetic resonance spectroscopy; exercise; fuel selection; insulin sensitivity; mitochondria; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2023.1208186
Basic Res Cardiol. 2023 Jul 26. 118(1): 29

Matrix metalloproteinase-2 proteolyzes mitofusin-2 and impairs mitochondrial function during myocardial ischemia-reperfusion injury.

Wesam Bassiouni, Robert Valencia, Zabed Mahmud, John M Seubert, Richard Schulz.

  During myocardial ischemia and reperfusion (IR) injury matrix metalloproteinase-2 (MMP-2) is rapidly activated in response to oxidative stress. MMP-2 is a multifunctional protease that cleaves both extracellular and intracellular proteins. Oxidative stress also impairs mitochondrial function which is regulated by different proteins, including mitofusin-2 (Mfn-2), which is lost in IR injury. Oxidative stress and mitochondrial dysfunction trigger the NLRP3 inflammasome and the innate immune response which invokes the de novo expression of an N-terminal truncated isoform of MMP-2 (NTT-MMP-2) at or near mitochondria. We hypothesized that MMP-2 proteolyzes Mfn-2 during myocardial IR injury, impairing mitochondrial function and enhancing the inflammasome response. Isolated hearts from mice subjected to IR injury (30 min ischemia/40 min reperfusion) showed a significant reduction in left ventricular developed pressure (LVDP) compared to aerobically perfused hearts. IR injury increased MMP-2 activity as observed by gelatin zymography and increased degradation of troponin I, an intracellular MMP-2 target. MMP-2 preferring inhibitors, ARP-100 or ONO-4817, improved post-ischemic recovery of LVDP compared to vehicle perfused IR hearts. In muscle fibers isolated from IR hearts the rates of mitochondrial oxygen consumption and ATP production were impaired compared to those from aerobic hearts, whereas ARP-100 or ONO-4817 attenuated these reductions. IR hearts showed higher levels of NLRP3, cleaved caspase-1 and interleukin-1β in the cytosolic fraction, while the mitochondria-enriched fraction showed reduced levels of Mfn-2, compared to aerobic hearts. ARP-100 or ONO-4817 attenuated these changes. Co-immunoprecipitation showed that MMP-2 is associated with Mfn-2 in aerobic and IR hearts. ARP-100 or ONO-4817 also reduced infarct size and cell death in hearts subjected to 45 min ischemia/120 min reperfusion. Following myocardial IR injury, impaired contractile function and mitochondrial respiration and elevated inflammasome response could be attributed, at least in part, to MMP-2 activation, which targets and cleaves mitochondrial Mfn-2. Inhibition of MMP-2 activity protects against cardiac contractile dysfunction in IR injury in part by preserving Mfn-2 and suppressing inflammation.

Keywords:  Inflammasomes; Ischemia–reperfusion injury; Matrix metalloproteinase-2; Mitochondria; Mitofusin-2

DOI:  https://doi.org/10.1007/s00395-023-00999-y
Front Mol Neurosci. 2023 ;16 1216947

High-altitude cerebral hypoxia promotes mitochondrial dysfunction and apoptosis of mouse neurons.

Yu Huan, Huilin Quan, Bo Jia, Guangzhi Hao, Zuolin Shi, Tianzi Zhao, Ying Yuan, Fang Yuan, Yushu Dong, Guobiao Liang.

   Introduction: Neuronal cell death is an important factor in the pathogenesis of acute high-altitude cerebral hypoxia; however, the underlying molecular mechanism remains unclear. In this study, we tested if high-altitude hypoxia (HAH) causes neuronal death and mitochondrial dysfunction using various in vivo and in vitro approaches.
Methods: Acute high-altitude cerebral hypoxia was induced by hypobaric hypoxia chamber in male mice. we explored the mechanisms of neuronal cell death using immunofluorescence, western blotting, transmission electron microscopy, and flow cytometry. Next, mitochondrial function and morphology were observed using Jc-1 staining, seahorse assay, western blotting, MitoTracker staining, and transmission electron microscopy. Moreover, open field test, elevated plus test, and Morris water maze were applied for animal behavior.
Results: Results revealed that HAH disrupted mitochondrial function and promoted neuronal apoptosis and necroptosis both in HT-22 cells and in mouse hippocampal neurons. Moreover, the mitochondrial membrane potential and adenosine triphosphate production decreased in neurons after HAH, while oxidative stress and mitochondrial fission increased. Behavioral studies suggested that HAH induced anxiety-like behavior and impaired spatial memory, while it had no effect on athletic ability.
Discussion: These findings demonstrated that HAH promotes mitochondrial dysfunction and apoptosis of mouse neurons, thus providing new insights into the role of mitochondrial function and neuronal cell death in acute high-altitude cerebral hypoxia.

Keywords:  apoptosis; high-altitude hypoxia; mitochondrial fission; necroptosis; neurons

DOI:  https://doi.org/10.3389/fnmol.2023.1216947
J Transl Med. 2023 Jul 28. 21(1): 512

RNA binding protein: coordinated expression between the nuclear and mitochondrial genomes in tumors.

Jiaoyan Ma, Liankun Sun, Weinan Gao, Yang Li, Delu Dong.

  Mitochondria are the only organelles regulated by two genomes. The coordinated translation of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), which together co-encode the subunits of the oxidative phosphorylation (OXPHOS) complex, is critical for determining the metabolic plasticity of tumor cells. RNA-binding protein (RBP) is a post-transcriptional regulatory factor that plays a pivotal role in determining the fate of mRNA. RBP rapidly and effectively reshapes the mitochondrial proteome in response to intracellular and extracellular stressors, mediating the cytoplasmic and mitochondrial translation balance to adjust mitochondrial respiratory capacity and provide energy for tumor cells to adapt to different environmental pressures and growth needs. This review highlights the ability of RBPs to use liquid-liquid phase separation (LLPS) as a platform for translation regulation, integrating nuclear-mitochondrial positive and retrograde signals to coordinate cross-department translation, reshape mitochondrial energy metabolism, and promote the development and survival of tumor cells.

Keywords:  Cytoplasmic translation; LLPS; Mitochondrial translation; OXPHOS; Retrograde signals

DOI:  https://doi.org/10.1186/s12967-023-04373-3
Antioxid Redox Signal. 2023 Jul 29.

SIRT5 alleviates liver ischemia/reperfusion injury by regulating mitochondrial succinylation and oxidative stress.

Jihong Yao, Yan Hu, Xinyao Tian, Yan Zhao, Zhecheng Wang, Musen Lin, Ruimin Sun, Yue Wang, Zhanyu Wang, Guiru Li, Shusen Zheng.

   AIMS: Mitochondrial dysfunction is the primary mechanism of liver ischemia/reperfusion (I/R) injury. The lysine desuccinylase sirtuin 5 (SIRT5) is a global regulator of the mitochondrial succinylome and has pivotal roles in mitochondrial metabolism and function; however, its hepatoprotective capacity in liver I/R remains unclear. Here, we established liver I/R model in SIRT5-silenced and SIRT5-overexpressed mice to examine the role and precise mechanisms of SIRT5 in liver I/R injury.
RESULTS: Succinylation was strongly enriched in liver mitochondria during I/R, and inhibiting mitochondrial succinylation significantly attenuated liver I/R injury. Importantly, the levels of the desuccinylase SIRT5 were notably decreased in liver transplant patients, as well as in mice subjected to I/R and in AML12 cells exposed to H/R. Furthermore, SIRT5 significantly ameliorated liver I/R-induced oxidative injury, apoptosis and inflammation by regulating mitochondrial oxidative stress and function. Intriguingly, the hepatoprotective effect of SIRT5 was mediated by PRDX3. Mechanistically, SIRT5 specifically desuccinylated PRDX3 at the K84 site, which enabled PRDX3 to alleviate mitochondrial oxidative stress during liver I/R.
INNOVATION: This study denoted the new effect and mechanism of SIRT5 in regulating mitochondrial oxidative stress through lysine desuccinylation, thus preventing liver I/R injury.
CONCLUSION: Our findings demonstrate for the first time that SIRT5 is a key mediator of liver I/R that regulates mitochondrial oxidative stress through the desuccinylation of PRDX3, which provides a novel strategy to prevent liver I/R injury.

Keywords:  PRDX3 mitochondrial oxidative stress.; SIRT5; liver ischemia/reperfusion; succinylation

DOI:  https://doi.org/10.1089/ars.2022.0137
Heliyon. 2023 Jun;9(6): e17167

Hypoxia inducible factor-1α is an important regulator of macrophage biology.

Bingquan Qiu, Piaoliu Yuan, Xiaojuan Du, Hongfang Jin, Junbao Du, Yaqian Huang.

  Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor composed of the α and β subunits, regulates cellular adaptive responses to hypoxia. Macrophages, which are derived from monocytes, function as antigen-presenting cells that activate various immune responses. HIF-1α regulates the immune response, viability, migration, phenotypic plasticity, and metabolism of macrophages. Specifically, macrophage-derived HIF-1α can prevent excessive pro-inflammatory responses by attenuating the transcriptional activity of nuclear factor-kappa B in vivo and in vitro. HIF-1α modulates macrophage migration by inducing the release of various chemokines and providing necessary energy. HIF-1α promotes macrophage M1 polarization by targeting glucose metabolism. Additionally, HIF-1α induces the upregulation of glycolysis-related enzymes and intermediates of the tricarboxylic acid cycle and pentose phosphate pathway. HIF-1α promotes macrophage apoptosis, necroptosis and reduces autophagy. The current review highlights the mechanisms associated with the regulation of HIF-1α stabilization in macrophages as well as the role of HIF-1α in modulating the physiological functions of macrophages.

Keywords:  Biology; Diseases; HIF-1α; Macrophage; Stability

DOI:  https://doi.org/10.1016/j.heliyon.2023.e17167
Biology (Basel). 2023 Jul 14. pii: 1005. [Epub ahead of print]12(7):

Exploring the Role of NCX1 and NCX3 in an In Vitro Model of Metabolism Impairment: Potential Neuroprotective Targets for Alzheimer's Disease.

Alessandra Preziuso, Silvia Piccirillo, Giorgia Cerqueni, Tiziano Serfilippi, Valentina Terenzi, Antonio Vinciguerra, Monia Orciani, Salvatore Amoroso, Simona Magi, Vincenzo Lariccia.

  Alzheimer's disease (AD) is a widespread neurodegenerative disorder, affecting a large number of elderly individuals worldwide. Mitochondrial dysfunction, metabolic alterations, and oxidative stress are regarded as cooperating drivers of the progression of AD. In particular, metabolic impairment amplifies the production of reactive oxygen species (ROS), resulting in detrimental alterations to intracellular Ca2+ regulatory processes. The Na+/Ca2+ exchanger (NCX) proteins are key pathophysiological determinants of Ca2+ and Na+ homeostasis, operating at both the plasma membrane and mitochondria levels. Our study aimed to explore the role of NCX1 and NCX3 in retinoic acid (RA) differentiated SH-SY5Y cells treated with glyceraldehyde (GA), to induce impairment of the default glucose metabolism that typically precedes Aβ deposition or Tau protein phosphorylation in AD. By using an RNA interference-mediated approach to silence either NCX1 or NCX3 expression, we found that, in GA-treated cells, the knocking-down of NCX3 ameliorated cell viability, increased the intracellular ATP production, and reduced the oxidative damage. Remarkably, NCX3 silencing also prevented the enhancement of Aβ and pTau levels and normalized the GA-induced decrease in NCX reverse-mode activity. By contrast, the knocking-down of NCX1 was totally ineffective in preventing GA-induced cytotoxicity except for the increase in ATP synthesis. These findings indicate that NCX3 and NCX1 may differently influence the evolution of AD pathology fostered by glucose metabolic dysfunction, thus providing a potential target for preventing AD.

Keywords:  Alzheimer’s disease; NCX; calcium homeostasis; energy metabolism impairment; oxidative stress

DOI:  https://doi.org/10.3390/biology12071005
Metabolites. 2023 Jul 23. pii: 875. [Epub ahead of print]13(7):

Metabolomic and Lipidomic Analysis of the Colorectal Adenocarcinoma Cell Line HT29 in Hypoxia and Reoxygenation.

Juan Carlos Alarcon Barrera, Alejandro Ondo-Mendez, Martin Giera, Sarantos Kostidis.

  The poor availability of oxygen and nutrients in malignant tumors drives the activation of various molecular responses and metabolic reprogramming in cancer cells. Hypoxic tumor regions often exhibit resistance to chemotherapy and radiotherapy. One approach to enhance cancer therapy is to indirectly increase tumor oxygen availability through targeted metabolic reprogramming. Thus, understanding the underlying metabolic changes occurring during hypoxia and reoxygenation is crucial for improving therapy efficacy. In this study, we utilized the HT29 colorectal adenocarcinoma cell line as a hypoxia-reoxygenation model to investigate central carbon and lipid metabolism. Through quantitative NMR spectroscopy and flow injection analysis - differential mobility spectroscopy-tandem mass spectrometry (FIA-DMS-MS/MS) analysis, we observed alterations in components of mitochondrial metabolism, redox status, specific lipid classes, and structural characteristics of lipids during hypoxia and up to 24 h of reoxygenation. These findings contribute to our understanding of the metabolic changes occurring during reoxygenation and provide the basis for functional studies aimed at metabolic pathways in cancer cells.

Keywords:  colorectal adenocarcinoma; hypoxia; lipidomics; metabolomics; reoxygenation

DOI:  https://doi.org/10.3390/metabo13070875
Biomedicines. 2023 Jun 30. pii: 1868. [Epub ahead of print]11(7):

The Role of ATP-Binding Cassette Proteins in Stem Cell Pluripotency.

Prince Saini, Sharath Anugula, Yick W Fong.

  Pluripotent stem cells (PSCs) are highly proliferative cells that can self-renew indefinitely in vitro. Upon receiving appropriate signals, PSCs undergo differentiation and can generate every cell type in the body. These unique properties of PSCs require specific gene expression patterns that define stem cell identity and dynamic regulation of intracellular metabolism to support cell growth and cell fate transitions. PSCs are prone to DNA damage due to elevated replicative and transcriptional stress. Therefore, mechanisms to prevent deleterious mutations in PSCs that compromise stem cell function or increase the risk of tumor formation from becoming amplified and propagated to progenitor cells are essential for embryonic development and for using PSCs including induced PSCs (iPSCs) as a cell source for regenerative medicine. In this review, we discuss the role of the ATP-binding cassette (ABC) superfamily in maintaining PSC homeostasis, and propose how their activities can influence cellular signaling and stem cell fate decisions. Finally, we highlight recent discoveries that not all ABC family members perform only canonical metabolite and peptide transport functions in PSCs; rather, they can participate in diverse cellular processes from genome surveillance to gene transcription and mRNA translation, which are likely to maintain the pristine state of PSCs.

Keywords:  ABC transporters; cell signaling; glutathione; metabolism; phospholipids; pluripotency; reactive oxygen species

DOI:  https://doi.org/10.3390/biomedicines11071868
Biomolecules. 2023 Jul 17. pii: 1138. [Epub ahead of print]13(7):

Computational Analysis Reveals Unique Binding Patterns of Oxygenated and Deoxygenated Myoglobin to the Outer Mitochondrial Membrane.

Andriy Anishkin, Kiran Kumar Adepu, Dipendra Bhandari, Sean H Adams, Sree V Chintapalli.

  Myoglobin (Mb) interaction with the outer mitochondrial membrane (OMM) promotes oxygen (O2) release. However, comprehensive molecular details on specific contact regions of the OMM with oxygenated (oxy-) and deoxygenated (deoxy-)Mb are missing. We used molecular dynamics (MD) simulations to explore the interaction of oxy- and deoxy-Mb with the membrane lipids of the OMM in two lipid compositions: (a) a typical whole membrane on average, and (b) specifically the cardiolipin-enriched cristae region (contact site). Unrestrained relaxations showed that on average, both the oxy- and deoxy-Mb established more stable contacts with the lipids typical of the cristae contact site, then with those of the average OMM. However, in steered detachment simulations, deoxy-Mb clung more tightly to the average OMM, and oxy-Mb strongly preferred the contact sites of the OMM. The MD simulation analysis further indicated that a non-specific binding, mediated by local electrostatic interactions, existed between charged or polar groups of Mb and the membrane, for stable interaction. To the best of our knowledge, this is the first computational study providing the molecular details of the direct Mb-mitochondria interaction that assisted in distinguishing the preferred localization of oxy- and deoxy-Mb on the OMM. Our findings support the existing experimental evidence on Mb-mitochondrial association and shed more insights on Mb-mediated O2 transport for cellular bioenergetics.

Keywords:  diffusion; mitochondria; myoglobin

DOI:  https://doi.org/10.3390/biom13071138
Biology (Basel). 2023 Jul 13. pii: 995. [Epub ahead of print]12(7):

Targeting Endothelial HIF2α/ARNT Expression for Ischemic Heart Disease Therapy.

Karim Ullah, Lizhuo Ai, Zainab Humayun, Rongxue Wu.

  Ischemic heart disease (IHD) is a major cause of mortality and morbidity worldwide, with novel therapeutic strategies urgently needed. Endothelial dysfunction is a hallmark of IHD, contributing to its development and progression. Hypoxia-inducible factors (HIFs) are transcription factors activated in response to low oxygen levels, playing crucial roles in various pathophysiological processes related to cardiovascular diseases. Among the HIF isoforms, HIF2α is predominantly expressed in cardiac vascular endothelial cells and has a key role in cardiovascular diseases. HIFβ, also known as ARNT, is the obligate binding partner of HIFα subunits and is necessary for HIFα's transcriptional activity. ARNT itself plays an essential role in the development of the cardiovascular system, regulating angiogenesis, limiting inflammatory cytokine production, and protecting against cardiomyopathy. This review provides an overview of the current understanding of HIF2α and ARNT signaling in endothelial cell function and dysfunction and their involvement in IHD pathogenesis. We highlight their roles in inflammation and maintaining the integrity of the endothelial barrier, as well as their potential as therapeutic targets for IHD.

Keywords:  ARNT; HIF pathway; HIF2α; endothelial cell function; inflammation; ischemic heart disease

DOI:  https://doi.org/10.3390/biology12070995
Ageing Res Rev. 2023 Jul 23. pii: S1568-1637(23)00181-2. [Epub ahead of print] 102022

Age-related pathophysiological alterations in molecular stress markers and key modulators of hypoxia.

Pinky, Neha, Mohd Salman, Pratika Kumar, Mohammad Ahmed Khan, Azfar Jamal, Suhel Parvez.

  Alzheimer's disease (AD) is characterized by an adverse cellular environment and pathological alterations in distinct brain regions. The development is triggered or facilitated by a condition such as hypoxia or ischemia, or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Increasing evidence suggests that hypoxia may affect many pathological aspects of AD, including oxidative stress, mitochondrial dysfunction, ER stress, amyloidogenic processing of APP, and Aβ accumulation, which may collectively result in neurodegeneration. Further investigation into the relationship between hypoxia and AD may provide an avenue for the effective preservation and pharmacological treatment of this neurodegenerative disease. This review summarizes the effects of normoxia and hypoxia on AD pathogenesis and discusses the underlying mechanisms. Regulation of HIF-1α and the role of its key players, including P53, VEGF, and GLUT1, are also discussed.

Keywords:  Alzheimer’s disease; ER stress; HIF-1ɑ regulation; Hypoxia; Mitochondrial dysfunction; Normoxia

DOI:  https://doi.org/10.1016/j.arr.2023.102022
Cells. 2023 Jul 14. pii: 1850. [Epub ahead of print]12(14):

Reduced Tie2 in Microvascular Endothelial Cells Is Associated with Organ-Specific Adhesion Molecule Expression in Murine Health and Endotoxemia.

Peter J Zwiers, Jacqueline P F E Lucas, Rianne M Jongman, Matijs van Meurs, Eliane R Popa, Grietje Molema.

  Endothelial cells (ECs) in the microvasculature in organs are active participants in the pathophysiology of sepsis. Tyrosine protein kinase receptor Tie2 (Tek; Tunica interna Endothelial cell Kinase) is thought to play a role in their inflammatory response, yet data are inconclusive. We investigated acute endotoxemia-induced changes in the expression of Tie2 and inflammation-associated endothelial adhesion molecules E-selectin and VCAM-1 (vascular cell adhesion molecule-1) in kidneys and lungs in inducible, EC-specific Tie2 knockout mice. The extent of Tie2 knockout in healthy mice differed between microvascular beds, with low to absent expression in arterioles in kidneys and in capillaries in lungs. In kidneys, Tie2 mRNA dropped more than 70% upon challenge with lipopolysaccharide (LPS) in both genotypes, with no change in protein. In renal arterioles, tamoxifen-induced Tie2 knockout was associated with higher VCAM-1 protein expression in healthy conditions. This did not increase further upon challenge of mice with LPS, in contrast to the increased expression occurring in control mice. Also, in lungs, Tie2 mRNA levels dropped within 4 h after LPS challenge in both genotypes, while Tie2 protein levels did not change. In alveolar capillaries, where tamoxifen-induced Tie2 knockout did not affect the basal expression of either adhesion molecule, a 4-fold higher E-selectin protein expression was observed after exposure to LPS compared to controls. The here-revealed heterogeneous effects of absence of Tie2 in ECs in kidney and lung microvasculature in health and in response to acute inflammatory activation calls for further in vivo investigations into the role of Tie2 in EC behavior.

Keywords:  E-selectin; Tie2 knockout mouse model; VCAM-1; adhesion molecules; endothelial cells; endothelial heterogeneity; endotoxemia; inflammation; kidney; lung; microvasculature

DOI:  https://doi.org/10.3390/cells12141850
Heliyon. 2023 Jun;9(6): e17166

The protective roles of citrus flavonoids, naringenin, and naringin on endothelial cell dysfunction in diseases.

Joy A Adetunji, Kehinde D Fasae, Ayobami I Awe, Oluwatomiwa K Paimo, Ayodeji M Adegoke, Jacob K Akintunde, Mamello P Sekhoacha.

  The endothelial cells (ECs) make up the inner lining of blood vessels, acting as a barrier separating the blood and the tissues in several organs. ECs maintain endothelium integrity by controlling the constriction and relaxation of the vasculature, blood fluidity, adhesion, and migration. These actions of ECs are efficiently coordinated via an intricate signaling network connecting receptors, and a wide range of cellular macromolecules. ECs are naturally quiescent i.e.; they are not stimulated and do not proliferate. Upon infection or disease, ECs become activated, and this alteration is pivotal in the pathogenesis of a spectrum of human neurological, cardiovascular, diabetic, cancerous, and viral diseases. Considering the central position that ECs play in disease pathogenesis, therapeutic options have been targeted at improving ECs integrity, assembly, functioning, and health. The dietary intake of flavonoids present in citrus fruits has been associated with a reduced risk of endothelium dysfunction. Naringenin (NGN) and Naringin (NAR), major flavonoids in grapefruit, tomatoes, and oranges possess anti-inflammatory, antioxidant properties, and cell survival potentials, which improve the health of the vascular endothelium. In this review, we provide a comprehensive summary and present the advances in understanding of the mechanisms through which NGN and NAR modulate the biomarkers of vascular dysfunction and protect the endothelium against unresolved inflammation, oxidative stress, atherosclerosis, and angiogenesis. We also provide perspectives and suggest further studies that will help assess the efficacy of citrus flavonoids in the therapeutics of human vascular diseases.

Keywords:  Citrus flavonoids; Endothelial dysfunction; Microvasculature; Naringenin; Naringin; Therapeutics

DOI:  https://doi.org/10.1016/j.heliyon.2023.e17166
Cells. 2023 Jul 12. pii: 1834. [Epub ahead of print]12(14):

Chronic Intermittent Hypoxia-Induced Diaphragm Muscle Weakness Is NADPH Oxidase-2 Dependent.

Sarah E Drummond, David P Burns, Sarah El Maghrani, Oscar Ziegler, Vincent Healy, Ken D O'Halloran.

  Chronic intermittent hypoxia (CIH)-induced redox alterations underlie diaphragm muscle dysfunction. We sought to establish if NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS) underpin CIH-induced changes in diaphragm muscle, which manifest as impaired muscle performance. Adult male mice (C57BL/6J) were assigned to one of three groups: normoxic controls (sham); chronic intermittent hypoxia-exposed (CIH, 12 cycles/hour, 8 h/day for 14 days); and CIH + apocynin (NOX2 inhibitor, 2 mM) administered in the drinking water throughout exposure to CIH. In separate studies, we examined sham and CIH-exposed NOX2-null mice (B6.129S-CybbTM1Din/J). Apocynin co-treatment or NOX2 deletion proved efficacious in entirely preventing diaphragm muscle dysfunction following exposure to CIH. Exposure to CIH had no effect on NOX2 expression. However, NOX4 mRNA expression was increased following exposure to CIH in wild-type and NOX2 null mice. There was no evidence of overt CIH-induced oxidative stress. A NOX2-dependent increase in genes related to muscle regeneration, antioxidant capacity, and autophagy and atrophy was evident following exposure to CIH. We suggest that NOX-dependent CIH-induced diaphragm muscle weakness has the potential to affect ventilatory and non-ventilatory performance of the respiratory system. Therapeutic strategies employing NOX2 blockade may function as an adjunct therapy to improve diaphragm muscle performance and reduce disease burden in diseases characterised by exposure to CIH, such as obstructive sleep apnoea.

Keywords:  NADPH oxidase; chronic intermittent hypoxia; diaphragm; obstructive sleep apnoea

DOI:  https://doi.org/10.3390/cells12141834