Arachidonic Acid Metabolites of CYP450 Enzymes and HIF-1α Modulate Endothelium-Dependent Vasorelaxation in Sprague-Dawley Rats under Acute and Intermittent Hyperbaric Oxygenation

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Abstract

Acetylcholine-induced vasorelaxation (AChIR) and responses to reduced pO ₂ (hypoxia-induced relaxation (HIR), 0% O ₂) were assessed in vitro in aortic rings of healthy male Sprague-Dawley rats (N = 252) under hyperbaric (HBO ₂) protocols. The studied groups consisted of the CTRL group (untreated); the A-HBO ₂ group (single HBO ₂; 120 min of 100% O ₂ at 2.0 bars); the 24H-HBO ₂ group (examined 24 h after single exposure) and the 4D-HBO ₂ group (four consecutive days of single HBO ₂). AChIR, sensitivity to ACh and iNOS expression were decreased in the A-HBO ₂ group. HIR was prostanoid- and epoxyeicosatrienoic acid (EET)-mediated. HIF-1α expression was increased in the 24H-HBO ₂ and 4D-HBO ₂ groups. LW6 (HIF-1α inhibitor) decreased HIR in the 24H-HBO ₂ group. HBO ₂ affected the expression of COX-1 and COX-2. CYP2c11 expression was elevated in the 24H-HBO ₂ and 4D-HBO ₂ groups. Concentrations of arachidonic acid (AA) metabolites 14(15)-DiHET, 11(12)-DiHET and 8(9)-DiHET were increased in A-HBO ₂ and 24H-HBO _2. An increased concentration of 8(9)-EET was observed in the A-HBO ₂ and 24h-HBO ₂ groups vs. the CTRL and 4D-HBO ₂ groups, and an increased concentration of 5(6)-DiHET was observed in the 24H-HBO ₂ group vs. the 4D-HBO ₂ group. The 20-HETE concentration was increased in the A-HBO ₂ group. All were determined by LC-MS/MS of the aorta. The results show that AChIR in all groups is mostly NO-dependent. HIR is undoubtedly mediated by the CYP450 enzymes’ metabolites of AA, whereas HIF-1α contributes to restored HIR. Vasoconstrictor metabolites of CYP450 enzymes contribute to attenuated AChIR and HIR in A-HBO ₂.

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Most cited references 47

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Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1.

Dominador Manalo, Ashley Rowan, Tera Lavoie … (2005)

Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding angiogenic growth factors, which are secreted by hypoxic cells and stimulate endothelial cells, leading to angiogenesis. To determine whether HIF-1 also mediates cell-autonomous responses to hypoxia, we have compared gene expression profiles in arterial endothelial cells cultured under nonhypoxic versus hypoxic conditions and in nonhypoxic cells infected with adenovirus encoding beta-galactosidase versus a constitutively active form of HIF-1alpha (AdCA5). There were 245 gene probes that showed at least 1.5-fold increase in expression in response to hypoxia and in response to AdCA5; 325 gene probes showed at least 1.5-fold decrease in expression in response to hypoxia and in response to AdCA5. The largest category of genes down-regulated by both hypoxia and AdCA5 encoded proteins involved in cell growth/proliferation. Many genes up-regulated by both hypoxia and AdCA5 encoded cytokines/growth factors, receptors, and other signaling proteins. Transcription factors accounted for the largest group of HIF-1-regulated genes, indicating that HIF-1 controls a network of transcriptional responses to hypoxia in endothelial cells. Infection of endothelial cells with AdCA5 under nonhypoxic conditions was sufficient to induce increased basement membrane invasion and tube formation similar to the responses induced by hypoxia, indicating that HIF-1 mediates cell-autonomous activation of endothelial cells.

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Mechanisms underlying endothelial dysfunction in diabetes mellitus.

U Hink, H. Li, H Mollnau … (2001)

Incubation of endothelial cells in vitro with high concentrations of glucose activates protein kinase C (PKC) and increases nitric oxide synthase (NOS III) gene expression as well as superoxide production. The underlying mechanisms remain unknown. To address this issue in an in vivo model, diabetes was induced with streptozotocin in rats. Streptozotocin treatment led to endothelial dysfunction and increased vascular superoxide production, as assessed by lucigenin- and coelenterazine-derived chemiluminescence. The bioavailability of vascular nitric oxide (as measured by electron spin resonance) was reduced in diabetic aortas, although expression of endothelial NOS III (mRNA and protein) was markedly increased. NOS inhibition with N:(G)-nitro-L-arginine increased superoxide levels in control vessels but reduced them in diabetic vessels, identifying NOS as a superoxide source. Similarly, we found an activation of the NADPH oxidase and a 7-fold increase in gp91(phox) mRNA in diabetic vessels. In vitro PKC inhibition with chelerythrine reduced vascular superoxide in diabetic vessels, whereas it had no effect on superoxide levels in normal vessels. In vivo PKC inhibition with N:-benzoyl-staurosporine did not affect glucose levels in diabetic rats but prevented NOS III gene upregulation and NOS-mediated superoxide production, thereby restoring vascular nitric oxide bioavailability and endothelial function. The reduction of superoxide in vitro by chelerythrine and the normalization of NOS III gene expression and reduction of superoxide in vivo by N:-benzoyl-staurosporine point to a decisive role of PKC in mediating these phenomena and suggest a therapeutic potential of PKC inhibitors in the prevention or treatment of vascular complications of diabetes mellitus. The full text of this article is available at http://www.circresaha.org.

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Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing.

Ineke P Stolze, Christoph Wotzlaw, Utta Berchner-Pfannschmidt … (2003)

Hypoxia-inducible factor1 (HIF-1) is an essential transcription factor for cellular adaptation to decreased oxygen availability. In normoxia the oxygen-sensitive alpha-subunit of HIF-1 is hydroxylated on Pro564 and Pro402 and thus targeted for proteasomal degradation. Three human oxygen-dependent HIF-1 alpha prolyl hydroxylases (PHD1, PHD2, and PHD3) function as oxygen sensors in vivo. Furthermore, the asparagine hydroxylase FIH-1 (factor inhibiting HIF) has been found to hydroxylate Asp803 of the HIF-1 C-terminal transactivation domain, which results in the decreased ability of HIF-1 to bind to the transcriptional coactivator p300/CBP. We have fused these enzymes to the N-terminus of fluorescent proteins and transiently transfected the fusion proteins into human osteosarcoma cells (U2OS). Three-dimensional 2-photon confocal fluorescence microscopy showed that PHD1 was exclusively present in the nucleus, PHD2 and FIH-1 were mainly located in the cytoplasm and PHD3 was homogeneously distributed in cytoplasm and nucleus. Hypoxia did not influence the localisation of any enzyme under investigation. In contrast to FIH-1, each PHD inhibited nuclear HIF-1 alpha accumulation in hypoxia. All hydroxylases suppressed activation of a cotransfected hypoxia-responsive luciferase reporter gene. Endogenous PHD2mRNA and PHD3mRNA were hypoxia-inducible, whereas expression of PHD1mRNA and FIH-1mRNA was oxygen independent. We propose that PHDs and FIH-1 form an oxygen sensor cascade of distinct subcellular localisation.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 01 September 2020

Publication date Collection: September 2020

Volume: 21

Issue: 17

Electronic Location Identifier: 6353

Affiliations

[1 ]Institute and Department of Physiology and Immunology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia or zmihaljevic@ 123456mefos.hr (Z.M.); acosic@ 123456mefos.hr (A.M.); ana.stupin@ 123456mefos.hr (A.S.); nbdujmusic@ 123456mefos.hr (N.K.); aleksandar_mf@ 123456yahoo.com (A.K.)

[2 ]Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, 31000 Osijek, Croatia

[3 ]Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health Studies, Josip Juraj Strossmayer University of Osijek, Crkvena ul. 21, 31000 Osijek, Croatia

[4 ]Centre for Research and Knowledge Transfer in Biotechnology, University of Zagreb, Trg Republike Hrvatske 14, 10000 Zagreb, Croatia; ruza.frkanec@ 123456unizg.hr

[5 ]Department of Drug Metabolism and Pharmacokinetics, Fidelta Ltd., Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia; Branka.Tavcar@ 123456fidelta.eu (B.T.); Vanja.Kelava@ 123456fidelta.eu (V.K.)

[6 ]Radiation Chemistry and Dosimetry Laboratory, Division of Materials Chemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia; itartaro@ 123456irb.hr

[7 ]Department of Heart and Vascular Diseases, Osijek University Hospital, J. Huttlera 4, 31000 Osijek, Croatia

Author notes

[* ]Correspondence: ines.drenjancevic@ 123456mefos.hr ; Tel.: +385-91-224-14-06

Author information

Zrinka Mihaljević https://orcid.org/0000-0002-6631-071X

Ana Stupin https://orcid.org/0000-0002-7446-0021

Ivana Tartaro Bujak https://orcid.org/0000-0002-1396-164X

Nikolina Kolobarić https://orcid.org/0000-0002-5649-8317

Ines Drenjančević https://orcid.org/0000-0003-4964-7721

Article

Publisher ID: ijms-21-06353

DOI: 10.3390/ijms21176353

PMC ID: 7503979

SO-VID: 81bf909c-3e27-4498-9cb2-1db5f746d114

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Arachidonic Acid Metabolites of CYP450 Enzymes and HIF-1α Modulate Endothelium-Dependent Vasorelaxation in Sprague-Dawley Rats under Acute and Intermittent Hyperbaric Oxygenation

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Most cited references 47

Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1.

Mechanisms underlying endothelial dysfunction in diabetes mellitus.

Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing.

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