• Title, Summary, Keyword: hypoxia

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Hypoxia Enhances Nitric Oxide Synthesis by Upregulation of Inducible Nitric Oxide Synthase in Endothelial Cells

  • Rhee, Ki-Jong;Gwon, Sun-Yeong;Lee, Seunghyung
    • Biomedical Science Letters
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    • v.19 no.3
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    • pp.180-187
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    • 2013
  • Hypoxia is an integral part of the environment during luteolysis. In this study we examined whether hypoxia could directly stimulate endothelial cells to produce nitric oxide (NO). Endothelial cells were cultured in hypoxic (5% $O_2$) or normoxic (20% $O_2$) conditions and the levels of total NO, inducible NO and endothelial NO was measured. We found that hypoxia but not normoxia upregulated NO production. The increased NO levels correlated with increased inducible NO synthase (iNOS) expression whereas expression of endothelial NOS (eNOS) expression remained constant. Addition of the iNOS specific inhibitor 1400W to hypoxic cultures prevented NO production suggesting that hypoxia-induced NO production in endothelial cells was due mainly to upregulation of iNOS. We also found that prostaglandin $F_{2{\alpha}}$ (PGF) production was unaffected by hypoxia suggesting that upregulation of NO was not due to increased synthesis of PGF. In summary, we report that endothelial cells cultured under hypoxic conditions produce NO via the iNOS pathway. This study provides the importance of the relation between the hypoxic environment and the induction of NO by endothelial cells during regression of the corpus luteum in the ovary.

Suppression of Akt-HIF-1α signaling axis by diacetyl atractylodiol inhibits hypoxia-induced angiogenesis

  • Choi, Sik-Won;Lee, Kwang-Sik;Lee, Jin Hwan;Kang, Hyeon Jung;Lee, Mi Ja;Kim, Hyun Young;Park, Kie-In;Kim, Sun-Lim;Shin, Hye Kyoung;Seo, Woo Duck
    • BMB Reports
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    • v.49 no.9
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    • pp.508-513
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    • 2016
  • Hypoxia-inducible factor (HIF)-1α is a key regulator associated with tumorigenesis, angiogenesis, and metastasis. HIF-1α regulation under hypoxia has been highlighted as a promising therapeutic target in angiogenesis-related diseases. Here, we demonstrate that diacetyl atractylodiol (DAA) from Atractylodes japonica (A. japonica) is a potent HIF-1α inhibitor that inhibits the Akt signaling pathway. DAA dose-dependently inhibited hypoxia-induced HIF-1α and downregulated Akt signaling without affecting the stability of HIF-1α protein. Furthermore, DAA prevented hypoxia-mediated angiogenesis based on in vitro tube formation and in vivo chorioallantoic membrane (CAM) assays. Therefore, DAA might be useful for treatment of hypoxia-related tumorigenesis, including angiogenesis.

Disappearance of Hypoxic Pulmonary Vasoconstriction and $O_2$-Sensitive Nonselective Cationic Current in Arterial Myocytes of Rats Under Ambient Hypoxia

  • Yoo, Hae Young;Kim, Sung Joon
    • The Korean Journal of Physiology and Pharmacology
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    • v.17 no.5
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    • pp.463-468
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    • 2013
  • Acute hypoxia induces contraction of pulmonary artery (PA) to protect ventilation/perfusion mismatch in lungs. As for the cellular mechanism of hypoxic pulmonary vasoconstriction (HPV), hypoxic inhibition of voltage-gated $K^+$ channel (Kv) in PA smooth muscle cell (PASMC) has been suggested. In addition, our recent study showed that thromboxane $A_2$ ($TXA_2$) and hypoxia-activated nonselective cation channel ($I_{NSC}$) is also essential for HPV. However, it is not well understood whether HPV is maintained in the animals exposed to ambient hypoxia for two days (2d-H). Specifically, the associated electrophysiological changes in PASMCs have not been studied. Here we investigate the effects of 2d-H on HPV in isolated ventilated/perfused lungs (V/P lungs) from rats. HPV was almost abolished without structural remodeling of PA in 2d-H rats, and the lost HPV was not recovered by Kv inhibitor, 4-aminopyridine. Patch clamp study showed that the hypoxic inhibition of Kv current in PASMC was similar between 2d-H and control. In contrast, hypoxia and $TXA_2$-activated $I_{NSC}$ was not observed in PASMCs of 2d-H. From above results, it is suggested that the decreased $I_{NSC}$ might be the primary functional cause of HPV disappearance in the relatively early period (2 d) of hypoxia.

Study on Mechanical Responses Induced by Hypoxia in Porcine Isolated Cerebral Artery (돼지 적출뇌혈관의 저산소 유발 수축반응에 관하여)

  • Kim, Yoong
    • The Korean Journal of Pharmacology
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    • v.29 no.2
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    • pp.203-212
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    • 1993
  • This study was designed to observe hypoxia-induced mechanical responses of porcine cerebral artery and to clarify their possible mechanisms. Hypoxia produced a transient vasoconstriction, recovering to the basal tension within 10 min and subsequent reoxygenation produced a biphasic (relaxalion-contraction) response in rings with endothelium under resting tension. Hypoxia produced a further contraction in rings precontracted with KCl or $PGF_{2{\alpha}}$, and following reoxygenation caused only sustained relaxation. Removal of the endothelium and pretreatment with nimodipine or indomethacin markedly attenuated the hypoxia- and reoxygenation-induced contractions. The KCl-induced contraction was not affected in hypoxic state, but contractions induced by $PGF_{2{\alpha}}$ or endothelin (ET) were inhibited in the hypoxia, the latter being more sensitive to the hypoxia. Upon reoxygenation, the attenuated contraction rapidly recovered to the original tension. Both hypoxia and reoxygenation significantly increased cyclic GMP content in the intact preparations, but not in the endothelium-removed ones. Acetylcholine (ACh) produced concentration-dependent relaxations in the intact endothelial rings precontracted with $PGF_{2{\alpha}}$ or endothelin, and the ACh-induced relaxation was inhibited by removal of endothelium and by hypoxia. ACh also increased cyclic GMP content in tissues pretreated with $PGF_{2{\alpha}}$ and the increase of cyclic GMP was abolished in hypoxic state. These results suggest that hypoxia- and reoxygenation-induced contractions are dependent on endothelium and extracellular calcium, and related to the release of prostaglandin-like substance(s).

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THE PROCESS OF THE DEVELOPMENT OF HYPOXIA IN AN ABNORMAL BLOOD FLOW

  • Kwak, Min-Kyu;Shin, Byeong-Chun;Go, Jae-Gwi
    • Honam Mathematical Journal
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    • v.30 no.1
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    • pp.75-89
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    • 2008
  • Interrupted blood flow diminishes the concentration of oxygen in tissues. Hypoxia first appears in the region distal to the capillaries and grows throughout the entire t issue. However, the time-wise evolution of hypoxic area is diverse when some of capillaries are blocked in a multi-capillary domain with different oxygen squirt. The process of the development of hypoxia through time course is analyzed mathematically in the domain. Each source in steady state is controlled by a time sensitive function to simulate the occlusion.

Influence of Kamijihwang-hwan on the Hypoxic Damage of Cultured Cerebral Neurons from mouse and SK-N-MC cells (가미지황환이 저산소성 신경세포 손상에 미치는 영향)

  • Kyung Baek Yeun;Ju Sung Min;Kim Kun Jun;Kim Dae Keun;Kang Jeong Ho;Lee Young Chan;Lee Jun;Kim Young Mok;Jeon Byung Hun
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.17 no.4
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    • pp.1082-1091
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    • 2003
  • To elucidate the neuroprotective effect of Kamijihwang-hwan(KSH) on nerve cells damaged by hypoxia, the cytotoxic effects of exposure to hypoxia were determined by XTT, NR, MTT and SRB asssay. The activity of catalase and SOD was measured by spectrophometry, and TNF-α and PKC activity was measured after exposure to hypoxia and treatment of Kamijihwang-hwan(KSH) water extract(KJHWE). Also the neuroprotective effect of KJHWE was researched for the elucidation of neuroprotective mechanism. The results were as follows ; Hypoxia decreased cell viability measured by XTT, NR assay when cultured cerebral neurons were exposed to 95% N2/5% CO₂ for 2~26 minutes in these cultures and KJHWE inhibited the decrease of cell viability. H₂O₂ treatment decreased cell viability measured by MTT, and SRB assay when cultured cerebral neurons were exposed to 1-80 uM for 6 hours, but KJHWE inhibited the decrease of cell viability. Hypoxia decreased catalase and SOD activity, and also TNF-α and PKC activity in these cultured cerebral neurons, but KJHWE inhibited the decrease of the catalase and SOD activity in these cultures. Hypoxia triggered the apoptosis via caspase activation and internucleosomal DNA fragmentation. Also hypoxia stimulate the release of cytochrome c form mitochondria. KJHWE inhibited the apoptosis via caspase activation induced by hypoxia. From these results, it can be suggested that brain ischemia model induced hypoxia showed neurotoxity on cultured mouse cerebral neurons, and the KJHWE has the neuroprotective effect in blocking the neurotoxity induced by hypoxia in cultured mouse cerebral neurons.

Effects of Hypoxia on Root Growth and Anaerobic Fermentative Enzymes in Winter Cereal Seedlings (저산소 조건하에서 맥류 유묘의 근생장 및 혐기발효 효소의 반응)

  • Park Myoung Ryoul;Lim Jeong Hyun;Yoo Nam Hee;Kwon In Sook;Kim Jung Gon;Choi Kyung Gu;Yun Song Joong
    • KOREAN JOURNAL OF CROP SCIENCE
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    • v.50 no.6
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    • pp.400-405
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    • 2005
  • Wet-injury often occurs in upland cereals growing in the paddy field due to oxygen deficiency in the rhizosphere caused by excessive water in the soil. Under hypoxia, energy metabolism is diminished causing non­reversible damage to root cells. This study was conducted to investigate effects of hypoxia on root growth and enzymes involved in the fermentative energy metabolism in upland cereals including barley, wheat, rye and triticale. Young seedlings were subject to hypoxia for up to 7 days. Root fresh weight and dry weight were decreased significantly by hypoxia for 5 to 7 days in all cereal seedlings. Root growth retardation under hypoxia was lowest in barley. Hypoxia-induced increases in activity and isozyme expression of alcohol dehydrogenase (ADH) and lactate dehydrogenase (LDH) were commonly observed in roots of all cereal seedlings. The inherent ADH activity levels were higher in barley but the hypoxia-induced increases in ADH activities were lowest in barley than other cereals. The inherent LDH activity levels were lower in barley and the hypoxia-induced increases in LDH activities were lower in barley than other cereals. The results suggest the importance of the rapid enhancement of fermentative enzyme systems for increased tolerance to hypoxia.

Effects of Hypoxia on the Fertilization and Early Development of Sea Urchin, Strongylocentrotus nudus (둥근성게 (Strongylocentrotus nudus)의 수정과 초기 배발생에 미치는 빈산소의 영향)

  • Lee, Gun-Sup;Hwang, Jin-Ik;Chung, Young-Jae;Kim, Dong-Giun;Moh, Sang-Hyun;Chang, Man;Lee, Taek-Kyun
    • Journal of the Korea Academia-Industrial cooperation Society
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    • v.13 no.8
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    • pp.3785-3791
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    • 2012
  • Dissolved oxygen is one of the most important factors controlling growth in aquatic organisms. Hypoxia is generally defined as dissolved oxygen less than 2.8 mg $O_2/L$ (equivalent to 2 mL $O_2/L$ or 91.4 mM). Therefore, hypoxia zone can cause a serious problem in marine ecosystem. In this study, to investigate embryotoxic (fertilization and embryo development rates) effects of hypoxia on sea urchin Strongylocentrotus nudus were exposed to dissolved oxygen levels of 7.6 mg $O_2/L$ (normoxia) and 1.8 mg $O_2/L$ (hypoxia) for 2 days at $15^{\circ}C$ and 33 ‰. Also, Expression levels of stress related gene (HSP70) and antioxidant related gene (glutathione reductase) in the sea urchins exposed to hypoxia were confirmed by Immunoblotting and RT-PCR analysis. In results, we showed that developmental rates were dramatically reduced in hypoxia condition. Molecular analysis demonstrated that higher HSP70 (5.5 fold) and glutathione reductase gene (2.79 fold) were present in the sea urchin exposed to hypoxia. Our results suggested that hypoxia can cause the abnormal development and elicits a stress and antioxidant response on sea urchin.

Acute Hypoxia Activates an ENaC-like Channel in Rat Pheochromocytoma (PC12) Cells

  • Bae, Yeon Ju;Yoo, Jae-Cheal;Park, Nammi;Kang, Dawon;Han, Jaehee;Hwang, Eunmi;Park, Jae-Yong;Hong, Seong-Geun
    • The Korean Journal of Physiology and Pharmacology
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    • v.17 no.1
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    • pp.57-64
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    • 2013
  • Cells can resist and even recover from stress induced by acute hypoxia, whereas chronic hypoxia often leads to irreversible damage and eventually death. Although little is known about the response(s) to acute hypoxia in neuronal cells, alterations in ion channel activity could be preferential. This study aimed to elucidate which channel type is involved in the response to acute hypoxia in rat pheochromocytomal (PC12) cells as a neuronal cell model. Using perfusing solution saturated with 95% $N_2$ and 5% $CO_2$, induction of cell hypoxia was confirmed based on increased intracellular $Ca^{2+}$ with diminished oxygen content in the perfusate. During acute hypoxia, one channel type with a conductance of about 30 pS (2.5 pA at -80 mV) was activated within the first 2~3 min following onset of hypoxia and was long-lived for more than 300 ms with high open probability ($P_o$, up to 0.8). This channel was permeable to $Na^+$ ions, but not to $K^+$, $Ca^+$, and $Cl^-$ ions, and was sensitively blocked by amiloride (200 nM). These characteristics and behaviors were quite similar to those of epithelial sodium channel (ENaC). RT-PCR and Western blot analyses confirmed that ENaC channel was endogenously expressed in PC12 cells. Taken together, a 30-pS ENaC-like channel was activated in response to acute hypoxia in PC12 cells. This is the first evidence of an acute hypoxia-activated $Na^+$ channel that can contribute to depolarization of the cell.

Whole-genome Transcriptional Responses to Hypoxia in Respiration-proficient and Respiration-deficient Yeasts: Implication of the Mitochondrial Respiratory Chain in Oxygen-regulated Gene Expression (저산소 환경에 대한 전체 유전자 발현 반응에서 미토콘드리아 호흡계의 연루)

  • Lee, Bo Young;Lee, Jong-Hwan;Byun, June-Ho;Woo, Dong Kyun
    • Journal of Life Science
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    • v.26 no.10
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    • pp.1137-1152
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    • 2016
  • Cells sense, respond, and adapt to a low oxygen environment called hypoxia, which is widely involved in a variety of human diseases. Adaptation to low oxygen concentrations includes gene expression changes by inducing hypoxic genes and reducing aerobic genes. Recently, the mitochondrial respiratory chain has been implicated in the control of these oxygen-regulated genes when cells experience hypoxia. In order to obtain an insight into an effect of the mitochondrial respiratory chain on cellular response to hyxpoxia, we here examined whole genome transcript signatures of respiration-proficient and respiration-deficient budding yeasts exposed to hypoxia using DNA microarrays. By comparing whole transcriptomes to hypoxia in respiration-proficient and respiration-deficient yeasts, we found that there are several classes of oxygen-regulated genes. Some of them require the mitochondrial respiratory chain for their expression under hypoxia while others do not. We found that the majority of hypoxic genes and aerobic genes need the mitochondrial respiratory chain for their expression under hypoxia. However, we also found that there are some hypoxic and aerobic genes whose expression under hypoxia is independent of the mitochondrial respiratory chain. These results indicate a key involvement of the mitochondrial respiratory chain in oxygen-regulated gene expression and multiple mechanisms for controlling oxygen-regulated gene expression. In addition, we provided gene ontology analyses and computational promoter analyses for hypoxic genes identified in the study. Together with differentially regulated genes under hypoxia, these post-analysis data will be useful resources for understanding the biology of response to hypoxia.