scholarly journals Differential Responsiveness in VEGF Receptor Subtypes to Hypoxic Stress in Various Tissues of Plateau Animals

2017 ◽  
pp. 357-362 ◽  
Author(s):  
H.-C. XIE ◽  
J.-G. LI ◽  
J.-P. HE
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Receptor Subtypes ◽  
Vegf Receptor ◽  
Hypoxic Stress ◽  
Adaptive Responses ◽  
Sprague Dawley ◽  
Low Oxygen ◽  
Hypoxic Environment

With hypoxic stress, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) are elevated and their responses are altered in skeletal muscles of plateau animals [China Qinghai-Tibetan plateau pikas (Ochotona curzoniae)] as compared with control animals [normal lowland Sprague-Dawley (SD) rats]. The results indicate that HIF-1α and VEGF are engaged in physiological functions under hypoxic environment. The purpose of the current study was to examine the protein levels of VEGF receptor subtypes (VEGFRs: VEGFR-1, VEGFR-2 and VEGFR-3) in the end organs, namely skeletal muscle, heart and lung in response to hypoxic stress. ELISA and Western blot analysis were employed to determine HIF-1α and the protein expression of VEGFRs in control animals and plateau pikas. We further blocked HIF-1α signal to determine if HIF-1α regulates alternations in VEGFRs in those tissues. We hypothesized that responsiveness of VEGFRs in the major end organs of plateau animals is differential with insult of hypoxic stress and is modulated by low oxygen sensitive HIF-1α. Our results show that hypoxic stress induced by exposure of lower O2 for 6 h significantly increased the levels of VEGFR-2 in skeletal muscle, heart and lung and the increases were amplified in plateau pikas. Our results also demonstrate that hypoxic stress enhanced VEGFR-3 in lungs of plateau animals. Nonetheless, no significant alternations in VEGFR-1 were observed in those tissues with hypoxic stress. Moreover, we observed decreases of VEGFR-2 in skeletal muscle, heart and lung; and decreases of VEGFR-3 in lung following HIF-1α inhibition. Overall, our findings suggest that in plateau animals 1) responsiveness of VEGFRs is different under hypoxic environment; 2) amplified VEGFR-2 response appears in skeletal muscle, heart and lung, and enhanced VEGFR-3 response is mainly observed in lung; 3) HIF-1α plays a regulatory role in the levels of VEGFRs. Our results provide the underlying cellular and molecular mechanisms responsible for hypoxic environment in plateau animals, having an impact on research of physiological and ecological adaptive responses to acute or chronic hypoxic stress in humans who living at high attitude and who live at a normal sea level but suffer from hypoxic disorders.

scholarly journals Expression of HIF-1α and VEGF in Skeletal Muscle of Plateau Animals in Response to Hypoxic Stress

2014 ◽  
pp. 801-805
Author(s):  
H.-C. XIE ◽  
J.-P. HE ◽  
J.-F. ZHU ◽  
J.-G. LI
Keyword(s):  
Skeletal Muscle ◽  
Skeletal Muscles ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Stress ◽  
Sprague Dawley ◽  
Protein Levels ◽  
Sd Rats ◽  
Hypoxic Environment ◽  
Endothelial Growth Factor

Hypoxia-inducible factor-1α (HIF-1α) transcriptionally regulates expression of several target genes in protecting tissues against hypoxia. With hypoxic stress, vascular endothelial growth factor (VEGF) is a signal protein produced by cells and further contributes to improvement of vascular functions and restoring the oxygen supply to tissues. In this current study, we first hypothesized that the protein levels of HIF-1α and VEGF are reduced in skeletal muscles of plateau animals [China Qinghai-Tibetan plateau pikas (ochotona curzoniae)] in response to hypoxia as compared with control animals [normal lowland Sprague-Dawley (SD) rats]. We further hypothesized that HIF-1α plays a role in regulating expression of VEGF in skeletal muscle. Note that HIF-1α and VEGF were determined by using two-site immunoenzymatic assay (ELISA) methods. Our results demonstrated that hypoxic stress induced by exposure of lower O2 (6 h) significantly increased the levels of HIF-1α and VEGF in the oxidative and glycolytic muscles of SD rats and pikas (P<0.05 vs. normoxic conditions). Notably, the increases in HIF-1α and VEGF were significantly less in pikas (P<0.05, vs. SD controls) than in SD rats. In addition, a linear relationship was observed between amplified HIF-1α and VEGF in oxidative muscle (r=0.76 and P<0.01) and glycolytic muscle (r=0.72 and P<0.01) and inhibiting HIF-1α significantly decreased expression of VEGF induced by hypoxic stress in skeletal muscles (P<0.05). Overall, our findings suggest that (1) responsiveness of HIF-1α and VEGF in skeletal muscles to hypoxic stress is blunted in plateau animals, and (2) HIF-1α has a regulatory effect on VEGF under hypoxic environment.

scholarly journals Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1715
Author(s):  
Macus Hao-Ran Bao ◽  
Carmen Chak-Lui Wong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Effective Treatment ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Combination Therapies ◽  
Low Oxygen ◽  
Treatment Regimens

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

scholarly journals Hypoxic tumor microenvironment: Implications for cancer therapy

2020 ◽  
Vol 245 (13) ◽  
pp. 1073-1086
Author(s):  
Sukanya Roy ◽  
Subhashree Kumaravel ◽  
Ankith Sharma ◽  
Camille L Duran ◽  
Kayla J Bayless ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Tumor Vasculature ◽  
Therapeutic Strategies ◽  
Therapeutic Resistance ◽  
Low Oxygen ◽  
Cancer Types

Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, tumor metabolism, growth, and therapeutic resistance in different cancer types. A large number of these effects are mediated by the transcription factor hypoxia inducible factor 1⍺ (HIF-1⍺) which is activated by hypoxia. HIF1⍺ induces glycolytic genes and reduces mitochondrial respiration rate in hypoxic tumoral regions through modulation of various cells in tumor microenvironment like cancer-associated fibroblasts. Immune evasion driven by HIF-1⍺ further contributes to enhanced survival of cancer cells. By altering drug target expression, metabolic regulation, and oxygen consumption, hypoxia leads to enhanced growth and survival of cancer cells. Tumor cells in hypoxic conditions thus attain aggressive phenotypes and become resistant to chemo- and radio- therapies resulting in higher mortality. While a number of new therapeutic strategies have succeeded in targeting hypoxia, a significant improvement of these needs a more detailed understanding of the various effects and molecular mechanisms regulated by hypoxia and its effects on modulation of the tumor vasculature. This review focuses on the chief hypoxia-driven molecular mechanisms and their impact on therapeutic resistance in tumors that drive an aggressive phenotype. Impact statement Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.

scholarly journals A MicroRNA Signature of Hypoxia

2006 ◽  
Vol 27 (5) ◽  
pp. 1859-1867 ◽  
Author(s):  
Ritu Kulshreshtha ◽  
Manuela Ferracin ◽  
Sylwia E. Wojcik ◽  
Ramiro Garzon ◽  
Hansjuerg Alder ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Hypoxia Inducible Factor ◽  
Tumor Formation ◽  
Low Oxygen ◽  
Functional Link ◽  
Factors Affecting ◽  
Cellular Processes ◽  
Hypoxic Environment ◽  
Tumorigenic Transformation ◽  
First Time

ABSTRACT Recent research has identified critical roles for microRNAs in a large number of cellular processes, including tumorigenic transformation. While significant progress has been made towards understanding the mechanisms of gene regulation by microRNAs, much less is known about factors affecting the expression of these noncoding transcripts. Here, we demonstrate for the first time a functional link between hypoxia, a well-documented tumor microenvironment factor, and microRNA expression. Microarray-based expression profiles revealed that a specific spectrum of microRNAs (including miR-23, -24, -26, -27, -103, -107, -181, -210, and -213) is induced in response to low oxygen, at least some via a hypoxia-inducible-factor-dependent mechanism. Select members of this group (miR-26, -107, and -210) decrease proapoptotic signaling in a hypoxic environment, suggesting an impact of these transcripts on tumor formation. Interestingly, the vast majority of hypoxia-induced microRNAs are also overexpressed in a variety of human tumors.

Gene expression profile of zebrafish exposed to hypoxia during development

2003 ◽  
Vol 13 (2) ◽  
pp. 97-106 ◽  
Author(s):  
Christopher Ton ◽  
Dimitri Stamatiou ◽  
Choong-Chin Liew
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Cdna Microarray ◽  
Expression Profile ◽  
Clinical Implications ◽  
Zebrafish Embryos ◽  
Hypoxic Stress ◽  
Microarray Technology ◽  
Adaptive Responses ◽  
Low Oxygen

Understanding how vertebrates respond to hypoxia can have important clinical implications. Fish have evolved the ability to survive long exposure to low oxygen levels. However, little is known about the specific changes in gene expression that result from hypoxia. In this study we used a zebrafish cDNA microarray to examine the expression of >4,500 genes in zebrafish embryos exposed to 24 h of hypoxia during development. We tested the hypotheses that hypoxia changes gene expression profile of the zebrafish embryos and that these changes can be reverted by reexposure to a normoxic (20.8% O2) environment. Our data were consistent with both of these hypotheses: indicating that zebrafish embryos undergo adaptive changes in gene expression in response to hypoxia. Our study provides a striking genetic portrait of the zebrafish embryos’ adaptive responses to hypoxic stress and demonstrates the utility of the microarray technology as a tool for analyzing complex developmental processes in the zebrafish.

scholarly journals The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb

2013 ◽  
Vol 304 (2) ◽  
pp. E229-E236 ◽  
Author(s):  
Andrew R. Kelleher ◽  
Scot R. Kimball ◽  
Michael D. Dennis ◽  
Rudolf J. Schilder ◽  
Leonard S. Jefferson
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Molecular Mechanisms ◽  
Bed Rest ◽  
Disuse Atrophy ◽  
Sprague Dawley ◽  
Ribosomal Protein S6 ◽  
Sprague Dawley Rats ◽  
Mtorc1 Signaling ◽  
Limb Immobilization

Limb immobilization, limb suspension, and bed rest cause substantial loss of skeletal muscle mass, a phenomenon termed disuse atrophy. To acquire new knowledge that will assist in the development of therapeutic strategies for minimizing disuse atrophy, the present study was undertaken with the aim of identifying molecular mechanisms that mediate control of protein synthesis and mechanistic target of rapamycin complex 1 (mTORC1) signaling. Male Sprague-Dawley rats were subjected to unilateral hindlimb immobilization for 1, 2, 3, or 7 days or served as nonimmobilized controls. Following an overnight fast, rats received either saline or l-leucine by oral gavage as a nutrient stimulus. Hindlimb skeletal muscles were extracted 30 min postgavage and analyzed for the rate of protein synthesis, mRNA expression, phosphorylation state of key proteins in the mTORC1 signaling pathway, and mTORC1 signaling repressors. In the basal state, mTORC1 signaling and protein synthesis were repressed within 24 h in the soleus of an immobilized compared with a nonimmobilized hindlimb. These responses were accompanied by a concomitant induction in expression of the mTORC1 repressors regulated in development and DNA damage responses (REDD) 1/2. The nutrient stimulus produced an elevation of similar magnitude in mTORC1 signaling in both the immobilized and nonimmobilized muscle. In contrast, phosphorylation of 70-kDa ribosomal protein S6 kinase 1 (p70S6K1) on Thr229 and Thr389 in response to the nutrient stimulus was severely blunted. Phosphorylation of Thr229 by PDK1 is a prerequisite for phosphorylation of Thr389 by mTORC1, suggesting that signaling through PDK1 is impaired in response to immobilization. In conclusion, the results show an immobilization-induced attenuation of mTORC1 signaling mediated by induction of REDD1/2 and defective p70S6K1 phosphorylation.

Mechanism of ischemic tolerance induced by hyperbaric oxygen preconditioning involves upregulation of hypoxia-inducible factor-1α and erythropoietin in rats

2008 ◽  
Vol 104 (4) ◽  
pp. 1185-1191 ◽  
Author(s):  
Guo-Jun Gu ◽  
Yun-Ping Li ◽  
Zao-Yun Peng ◽  
Jia-Jun Xu ◽  
Zhi-Min Kang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Hyperbaric Oxygen ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Focal Cerebral Ischemia ◽  
Hypoxia Inducible Factor ◽  
Sprague Dawley ◽  
Triphenyltetrazolium Chloride ◽  
Time Points ◽  
Hypoxia Inducible Factor 1Α

We studied the effect of hyperbaric oxygen (HBO) preconditioning on the molecular mechanisms of neuroprotection in a rat focal cerebral ischemic model. Seventy-two male Sprague-Dawley rats were pretreated with HBO (100% O2, 2 atmospheres absolute, 1 h once every other day for 5 sessions) or with room air. In experiment 1, HBO-preconditioned rats and matched room air controls were subjected to focal cerebral ischemia or sham surgery. Postinjury motor parameters and infarction volumes of HBO-preconditioned rats were compared with those of controls. In experiment 2, HBO-preconditioned rats and matched room air controls were killed at different time points. Brain levels of hypoxia-inducible factor-1α (HIF-1α) and its downstream target gene erythropoietin (EPO) analyzed by Western blotting and RT-PCR as well as HIF-1α DNA-binding and transcriptional activities were determined in the ipsilateral hemisphere. HBO induced a marked increase in the protein expressions of HIF-1α and EPO and the activity of HIF-1α, as well as the expression of EPO mRNA. HBO preconditioning dramatically improved the neurobehavioral outcome at all time points (3.0 ± 2.1 vs. 5.6 ± 1.5 at 4 h, 5.0 ± 1.8 vs. 8.8 ± 1.4 at 8 h, 6.4 ± 1.8 vs. 9.7 ± 1.3 at 24 h; P < 0.01, respectively) and reduced infarction volumes (20.7 ± 4.5 vs. 12.5 ± 3.6%, 2,3,5-Triphenyltetrazolium chloride staining) after cerebral ischemia. This observation indicates that the neuroprotection induced by HBO preconditioning may be mediated by an upregulation of HIF-1α and its target gene EPO.

scholarly journals Xenon Upregulates Hypoxia Inducible Factor 1 Alpha in Neonatal Rat Brain under Normoxic Conditions

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Simona Valleggi ◽  
Chirag B. Patel ◽  
Andrea O. Cavazzana ◽  
Daqing Ma ◽  
Francesco Giunta ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Hypoxia Inducible Factor ◽  
Neonatal Rat ◽  
Transcript Analysis ◽  
Sprague Dawley ◽  
Organ Protection ◽  
Minute Exposure ◽  
Hypoxia Inducible Factor 1 ◽  
Significant Difference

Xenon can induce cell and organ protection through different molecular mechanisms related to oxygen level. We explored the effect of xenon on oxygen-related signalling in the central nervous system via hypoxia inducible factor 1 alpha (HIF-1α) and mammalian target of rapamycin (mTOR). Methods. Postnatal day 7 (P7) Sprague Dawley rats were exposed to 25% oxygen/75% nitrogen (air group) or 25% oxygen/75% xenon (treatment group) for 120 min. Brains were collected immediately (transcript analysis—relative real-time polymerase chain reaction) or 24 hours (protein analysis—immunohistochemistry) after the 120-minute exposure period; peak anesthetic preconditioning has been previously identified at 24 hours post-exposure. Results. HIF-1α transcript and protein levels were found to be increased in xenon-exposed compared to air-exposed brains. Sustained nuclear translocation of the protein, accounting for an increased activity of HIF-1α, was also noted. mTOR transcript analysis revealed no significant difference between xenon-exposed and air-exposed brains immediately after the 120-minute exposure. Conclusion. Our data suggest that xenon induces the upregulation of HIF-1α transcription and translation, which may contribute to xenon's neuroprotective preconditioning effect. However, given that xenon exposure did not affect mTOR transcription, further investigation into other signalling cascades mediating xenon’s effects on HIF-1α in developing brain is warranted.

scholarly journals Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction

2021 ◽  
Vol 23 (1) ◽  
pp. 169
Author(s):  
Lisa A. Walter ◽  
Lauren P. Blake ◽  
Yann S. Gallot ◽  
Charles J. Arends ◽  
Randall S. Sozio ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sciatic Nerve ◽  
Neuromuscular Junction ◽  
Molecular Mechanisms ◽  
Skeletal Muscle Atrophy ◽  
Sprague Dawley ◽  
Unfolded Protein ◽  
Potential Therapeutic Role ◽  
The Unfolded Protein Response ◽  
Protein Response

Denervation of skeletal muscle is a debilitating consequence of injury of the peripheral nervous system, causing skeletal muscle to experience robust atrophy. However, the molecular mechanisms controlling the wasting of skeletal muscle due to denervation are not well understood. Here, we demonstrate that transection of the sciatic nerve in Sprague–Dawley rats induced robust skeletal muscle atrophy, with little effect on the neuromuscular junction (NMJ). Moreover, the following study indicates that all three arms of the unfolded protein response (UPR) are activated in denervated skeletal muscle. Specifically, ATF4 and ATF6 are elevated in the cytoplasm of skeletal muscle, while XBP1 is elevated in the nuclei of skeletal muscle. Moreover, XBP1 is expressed in the nuclei surrounding the NMJ. Altogether, these results endorse a potential role of the UPR and, specifically, XBP1 in the maintenance of both skeletal muscle and the NMJ following sciatic nerve transection. Further investigations into a potential therapeutic role concerning these mechanisms are needed.

scholarly journals Altitude, Exercise, and Skeletal Muscle Angio-Adaptive Responses to Hypoxia: A Complex Story

2021 ◽  
Vol 12 ◽  
Author(s):  
Pierre Lemieux ◽  
Olivier Birot
Keyword(s):  
Skeletal Muscle ◽  
Cellular Level ◽  
Hypoxic Stress ◽  
Adaptive Responses ◽  
Skeletal Muscle Function ◽  
Pathological Conditions ◽  
Molecular Complexity ◽  
Exercise Induced ◽  
Ambient Hypoxia ◽  
Muscle Capillaries

Hypoxia, defined as a reduced oxygen availability, can be observed in many tissues in response to various physiological and pathological conditions. As a hallmark of the altitude environment, ambient hypoxia results from a drop in the oxygen pressure in the atmosphere with elevation. A hypoxic stress can also occur at the cellular level when the oxygen supply through the local microcirculation cannot match the cells’ metabolic needs. This has been suggested in contracting skeletal myofibers during physical exercise. Regardless of its origin, ambient or exercise-induced, muscle hypoxia triggers complex angio-adaptive responses in the skeletal muscle tissue. These can result in the expression of a plethora of angio-adaptive molecules, ultimately leading to the growth, stabilization, or regression of muscle capillaries. This remarkable plasticity of the capillary network is referred to as angio-adaptation. It can alter the capillary-to-myofiber interface, which represent an important determinant of skeletal muscle function. These angio-adaptive molecules can also be released in the circulation as myokines to act on distant tissues. This review addresses the respective and combined potency of ambient hypoxia and exercise to generate a cellular hypoxic stress in skeletal muscle. The major skeletal muscle angio-adaptive responses to hypoxia so far described in this context will be discussed, including existing controversies in the field. Finally, this review will highlight the molecular complexity of the skeletal muscle angio-adaptive response to hypoxia and identify current gaps of knowledges in this field of exercise and environmental physiology.

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