scholarly journals Inhibition of hypoxia-inducible factor 1α accumulation by glyceryl trinitrate and cyclic guanosine monophosphate

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Judy Kim ◽  
Ivraym B. Barsoum ◽  
Harrison Loh ◽  
Jean-François Paré ◽  
D. Robert Siemens ◽  
...  
Keyword(s):  
Glyceryl Trinitrate ◽  
Hypoxia Inducible Factor ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Protein Accumulation ◽  
Dependent Manner ◽  
Adaptive Responses ◽  
Calpain Activity ◽  
Hypoxia Inducible Factor 1 ◽  
Cgmp Signalling

Abstract A key mechanism mediating cellular adaptive responses to hypoxia involves the activity of hypoxia-inducible factor 1 (HIF-1), a transcription factor composed of HIF-1α, and HIF-1β subunits. The classical mechanism of regulation of HIF-1 activity involves destabilisation of HIF-1α via oxygen-dependent hydroxylation of proline residues and subsequent proteasomal degradation. Studies from our laboratory revealed that nitric oxide (NO)-mediated activation of cyclic guanosine monophosphate (cGMP) signalling inhibits the acquisition of hypoxia-induced malignant phenotypes in tumour cells. The present study aimed to elucidate a mechanism of HIF-1 regulation involving NO/cGMP signalling. Using human DU145 prostate cancer cells, we assessed the effect of the NO mimetic glyceryl trinitrate (GTN) and the cGMP analogue 8-Bromo-cGMP on hypoxic accumulation of HIF-1α. Concentrations of GTN known to primarily activate the NO/cGMP pathway (100 nM–1 µM) inhibited hypoxia-induced HIF-1α protein accumulation in a time-dependent manner. Incubation with 8-Bromo-cGMP (1 nM–10 µM) also attenuated HIF-1α accumulation, while levels of HIF-1α mRNA remained unaltered by exposure to GTN or 8-Bromo-cGMP. Furthermore, treatment of cells with the calpain (Ca2+-activated proteinase) inhibitor calpastatin attenuated the effects of GTN and 8-Bromo-cGMP on HIF-1α accumulation. However, since calpain activity was not affected by incubation of DU145 cells with various concentrations of GTN or 8-Bromo-cGMP (10 nM or 1 µM) under hypoxic or well-oxygenated conditions, it is unlikely that NO/cGMP signalling inhibits HIF-1α accumulation via regulation of calpain activity. These findings provide evidence for a role of NO/cGMP signalling in the regulation of HIF-1α, and hence HIF-1-mediated hypoxic responses, via a mechanism dependent on calpain.

Polydatin Attenuates Carbachol-induced Contraction of Guinea Pig Gallbladder

2019 ◽  
Vol 18 (1) ◽  
pp. 34-38
Author(s):  
Chen Lei ◽  
Pan Xiang ◽  
Shen Yonggang ◽  
Song Kai ◽  
Zhong Xingguo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Guinea Pig ◽  
Smooth Muscles ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
Dose Dependent

The aim of this study was to determine whether polydatin, a glucoside of resveratrol isolated from the root of Polygonum cuspidatum, warranted development as a potential therapeutic for ameliorating the pain originating from gallbladder spasm disorders and the underlying mechanisms. Guinea pig gallbladder smooth muscles were treated with polydatin and specific inhibitors to explore the mechanisms underpinning polydatin-induced relaxation of carbachol-precontracted guinea pig gallbladder. Our results shown that polydatin relaxed carbachol-induced contraction in a dose-dependent manner through the nitric oxide/cyclic guanosine monophosphate/protein kinase G and the cyclic adenosine monophosphate/protein kinase A signaling pathways as well as the myosin light chain kinase and potassium channels. Our findings suggested that there was value in further exploring the potential therapeutic use of polydatin in gallbladder spasm disorders.

scholarly journals The Hypoxia-Inducible Factor 1/NOR-1 Axis Regulates the Survival Response of Endothelial Cells to Hypoxia

2009 ◽  
Vol 29 (21) ◽  
pp. 5828-5842 ◽  
Author(s):  
Lluis Martorell ◽  
Maurizio Gentile ◽  
Jordi Rius ◽  
Cristina Rodríguez ◽  
Javier Crespo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Orphan Receptor ◽  
Vegf Receptor ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Hypoxia Inducible Factor 1 ◽  
Apoptosis Protein

ABSTRACT Hypoxia induces apoptosis but also triggers adaptive mechanisms to ensure cell survival. Here we show that the prosurvival effects of hypoxia-inducible factor 1 (HIF-1) in endothelial cells are mediated by neuron-derived orphan receptor 1 (NOR-1). The overexpression of NOR-1 decreased the rate of endothelial cells undergoing apoptosis in cultures exposed to hypoxia, while the inhibition of NOR-1 increased cell apoptosis. Hypoxia upregulated NOR-1 mRNA levels in a time- and dose-dependent manner. Blocking antibodies against VEGF or SU5614 (a VEGF receptor 2 inhibitor) did not prevent hypoxia-induced NOR-1 expression, suggesting that NOR-1 is not induced by the autocrine secretion of VEGF in response to hypoxia. The reduction of HIF-1α protein levels by small interfering RNAs, or by inhibitors of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway or mTOR, significantly counteracted hypoxia-induced NOR-1 upregulation. Intracellular Ca2+ was involved in hypoxia-induced PI3K/Akt activation and in the downstream NOR-1 upregulation. A hypoxia response element mediated the transcriptional activation of NOR-1 induced by hypoxia as we show by transient transfection and chromatin immunoprecipitation assays. Finally, the attenuation of NOR-1 expression reduced both basal and hypoxia-induced cIAP2 (cellular inhibitor of apoptosis protein 2) mRNA levels, while NOR-1 overexpression upregulated cIAP2. Therefore, NOR-1 is a downstream effector of HIF-1 signaling involved in the survival response of endothelial cells to hypoxia.

Structural–Activity Relationship of Ginsenosides from Steamed Ginseng in the Treatment of Erectile Dysfunction

2018 ◽  
Vol 46 (01) ◽  
pp. 137-155 ◽  
Author(s):  
Ang Ying ◽  
Qing-Tao Yu ◽  
Li Guo ◽  
Wen-Song Zhang ◽  
Jin-Feng Liu ◽  
...  
Keyword(s):  
Erectile Dysfunction ◽  
Hypoxia Inducible Factor ◽  
Corpus Cavernosum ◽  
Cyclic Guanosine Monophosphate ◽  
Deficiency Syndrome ◽  
Guanosine Monophosphate ◽  
Hydroxyl Groups ◽  
Mice Model ◽  
Kidney Yang Deficiency ◽  
Relationship Of

Ginseng has been reported to have diverse pharmacological effects. One of the therapeutic claims for ginseng is to enhance sexual function. Ginsenosides are considered as the major active constituents. A steaming process can alter the ginsenoside profile of ginseng products. The structure–function relationship of ginsenosides in the treatment of erectile dysfunction (ED) has not been investigated yet. In this work, 15 different processed ginsengs are produced by steaming, and 13 major ginsensosides are quantified by liquid chromatography with UV detection, including Rg1, Re, Rf, Rb1, Rc, Rb2, Rf, Rk3, Rh4, 20S-Rg3, 20R-Rg3, Rk1, and Rg5. Their anti-ED activities are screened using hydrocortisone-induced mice model (Kidney Yang Deficiency Syndrome in Chinese Medicine) and primary corpus cavernosum smooth muscle cells (CCSMCs). A processed ginseng with steaming treatment at 120[Formula: see text]C for 4[Formula: see text]h and five times possesses abundant ginsenosides Rk1, Rk3, Rh4 and Rg5 transformed via deglycosylation and dehydroxylation, and produces optimal activity against ED. The number of sugar molecules, structure of hydroxyl groups and stereoselectivity in ginsenosides affect their anti-ED activity. Among the 13 ginsenosides, Rk1, Rk3, Rh4 and Rg5 are the most efficient in decreasing intracellular calcium levels by inhibiting phosphodiesterase 5A (PDE5A) to reduce the degradation of cyclic guanosine monophosphate (cGMP) in CCSMCs. Rg5 also restrain hypoxia inducible factor-1[Formula: see text] (HIF-1[Formula: see text] expression in hypoxia state, and increase endothelial nitric oxide synthase (eNOS) expression in isolated rat cavernous tissue. These observations suggest a role for steamed ginseng containing two pairs of geometric isomers (i.e., Rk1/Rg5 and Rk3/Rh4) in the treatment of ED.

scholarly journals Accelerated tumor growth under intermittent hypoxia is associated with hypoxia-inducible factor-1-dependent adaptive responses to hypoxia

Oncotarget ◽  
2017 ◽  
Vol 8 (37) ◽  
pp. 61592-61603 ◽  
Author(s):  
Dae Wui Yoon ◽  
Daeho So ◽  
Sra Min ◽  
Jiyoung Kim ◽  
Mingyu Lee ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Adaptive Responses ◽  
Hypoxia Inducible Factor 1

Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic

Science ◽  
2020 ◽  
Vol 369 (6506) ◽  
pp. 993-999 ◽  
Author(s):  
Emily N. Chin ◽  
Chenguang Yu ◽  
Vincent F. Vartabedian ◽  
Ying Jia ◽  
Manoj Kumar ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Receptor Activation ◽  
Guanosine Monophosphate ◽  
Dependent Manner ◽  
Biological Processes ◽  
Programmed Cell Death 1 ◽  
Cocrystal Structure ◽  
Cyclic Dinucleotide

Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) mimetic that induces the same “closed” conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.

Abstract 923: Dissociation Between Superoxide Accumulation And Nitroglycerin Induced Tolerance

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Vamsi K Addanki ◽  
Pei-Suen Tsou ◽  
Ho-Leung Fung
Keyword(s):  
Nadph Oxidase ◽  
Ex Vivo ◽  
Dry Weight ◽  
Causative Factor ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Protein Accumulation ◽  
Induced Tolerance

We hypothesize that superoxide (SO) accumulation is not a critical causative factor in inducing nitroglycerin (NTG) tolerance. Using p47phox−/− and gp91−/− mice vs. their respective wild-type (WT) controls, we showed that aorta from mice null of these critical NADPH oxidase subunits exhibited similar vascular tolerance after NTG dosing (20 mg/kg sc, tid for 3 days), as indicated by their ex vivo pEC 50 and cyclic guanosine monophosphate (cGMP, pmol/mg protein) accumulation upon NTG challenge. In vitro aorta SO production (cpm/mg dry weight) was enhanced by NTG incubation both in p47phox null and WT mice (Table 1 ). Pre-exposure of isolated mice aorta to 100 microM NTG for 1 hr resulted in vascular tolerance toward NTG and increased SO accumulation. Oxypurinol (Oxy, 1mM) reduced SO but failed to attenuate vascular tolerance (Table 2 ). In LLC-PK1 cells, pre-exposure to NTG (1 microM for 4 hours) resulted in increased SO accumulation and reduced cGMP response to 3.16 microM NTG vs. vehicle control. Exposure to 1 microM angiotensin II increased SO but did not reduce cGMP response. Taken together, these results indicate that in vivo vascular NTG tolerance in mice does not require the presence of the p47phox and gp91phox subunits of NADPH oxidase, and that increased SO accumulation may be a consequence, rather than a cause, of NTG tolerance. Table 1 Table 2

Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators

2018 ◽  
Vol 77 (3) ◽  
pp. 459-459 ◽  
Author(s):  
Alexandru-Emil Matei ◽  
Christian Beyer ◽  
Andrea-Hermina Györfi ◽  
Alina Soare ◽  
Chih-Wei Chen ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Transforming Growth Factor ◽  
Soluble Guanylate Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Transforming Growth Factor Β1 ◽  
Guanosine Monophosphate ◽  
Dependent Manner ◽  
Erk Phosphorylation ◽  
Sgc Stimulators

ObjectivesStimulators of soluble guanylate cyclase (sGC) are currently investigated in clinical trials for the treatment of fibrosis in systemic sclerosis (SSc). In this study, we aim to investigate the role of protein kinases G (PKG) as downstream mediators of sGC–cyclic guanosine monophosphate (cGMP) in SSc.MethodsMice with combined knockout of PKG1 and 2 were challenged with bleomycin and treated with the sGC stimulator BAY 41-2272. Fibroblasts were treated with BAY 41-2272 and with the PKG inhibitor KT 5823.ResultsPKG1 and 2 are upregulated in SSc in a transforming growth factor-β1 (TGFβ1)-dependent manner, as an attempt to compensate for the decreased signalling through the sGC–cGMP–PKG pathway. Inhibition or knockout of PKG1 and 2 abrogates the inhibitory effects of sGC stimulation on fibroblast activation in a SMAD-independent, but extracellular signal-regulated kinase (ERK)-dependent manner. In vivo, sGC stimulation fails to prevent bleomycin-induced fibrosis in PKG1 and 2 knockout mice.ConclusionsOur data provide evidence that PKGs are essential mediators of the antifibrotic effects of sGC stimulators through interfering with non-canonical TGFβ signalling. TGFβ1 promotes its profibrotic effects through inhibition of sGC–cGMP–PKG signalling, sGC stimulation exerts its antifibrotic effects by inhibition of TGFβ1-induced ERK phosphorylation.

Regulation of Oxygen Homeostasis by Hypoxia-Inducible Factor 1

Physiology ◽  
2009 ◽  
Vol 24 (2) ◽  
pp. 97-106 ◽  
Author(s):  
Gregg L. Semenza
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Systemic Hypertension ◽  
Adaptive Responses ◽  
Hypoxia Inducible Factor 1 ◽  
Oxygen Homeostasis ◽  
Genes Encoding

Metazoan organisms are dependent on a continuous supply of O2 for survival. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in development, physiology, and disease. HIF-1 activity is induced in response to continuous hypoxia, intermittent hypoxia, growth factor stimulation, and Ca2+ signaling. HIF-1 mediates adaptive responses to hypoxia, including erythropoiesis, angiogenesis, and metabolic reprogramming. In each case, HIF-1 regulates the expression of multiple genes encoding key components of the response pathway. HIF-1 also mediates maladaptive responses to chronic continuous and intermittent hypoxia, which underlie the development of pulmonary and systemic hypertension, respectively.

Sign in / Sign up

Export Citation Format

Share Document