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      Exposure to acute normobaric hypoxia results in adaptions of both the macro- and microcirculatory system

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          Abstract

          Although acute hypoxia is of utmost pathophysiologic relevance in health and disease, studies on its effects on both the macro- and microcirculation are scarce. Herein, we provide a comprehensive analysis of the effects of acute normobaric hypoxia on human macro- and microcirculation. 20 healthy participants were enrolled in this study. Hypoxia was induced in a normobaric hypoxia chamber by decreasing the partial pressure of oxygen in inhaled air stepwisely (pO 2; 21.25 kPa (0 k), 16.42 kPa (2 k), 12.63 kPa (4 k) and 9.64 kPa (6 k)). Macrocirculatory effects were assessed by cardiac output measurements, microcirculatory changes were investigated by sidestream dark-field imaging in the sublingual capillary bed and videocapillaroscopy at the nailfold. Exposure to hypoxia resulted in a decrease of systemic vascular resistance ( p < 0.0001) and diastolic blood pressure ( p = 0.014). Concomitantly, we observed an increase in heart rate ( p < 0.0001) and an increase of cardiac output ( p < 0.0001). In the sublingual microcirculation, exposure to hypoxia resulted in an increase of total vessel density, proportion of perfused vessels and perfused vessel density. Furthermore, we observed an increase in peripheral capillary density. Exposure to acute hypoxia results in vasodilatation of resistance arteries, as well as recruitment of microvessels of the central and peripheral microcirculation. The observed macro- and microcirculatory effects are most likely a result from compensatory mechanisms to ensure adequate tissue oxygenation.

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          Most cited references 45

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          Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions.

          Hypoxia-inducible factor (HIF-1) is an oxygen-dependent transcriptional activator, which plays crucial roles in the angiogenesis of tumors and mammalian development. HIF-1 consists of a constitutively expressed HIF-1beta subunit and one of three subunits (HIF-1alpha, HIF-2alpha or HIF-3alpha). The stability and activity of HIF-1alpha are regulated by various post-translational modifications, hydroxylation, acetylation, and phosphorylation. Therefore, HIF-1alpha interacts with several protein factors including PHD, pVHL, ARD-1, and p300/CBP. Under normoxia, the HIF-1alpha subunit is rapidly degraded via the von Hippel-Lindau tumor suppressor gene product (pVHL)- mediated ubiquitin-proteasome pathway. The association of pVHL and HIF-1alpha under normoxic conditions is triggered by the hydroxylation of prolines and the acetylation of lysine within a polypeptide segment known as the oxygen-dependent degradation (ODD) domain. On the contrary, in the hypoxia condition, HIF-1alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 are especially related to angiogenesis, cell proliferation/survival, and glucose/iron metabolism. Moreover, it was reported that the activation of HIF-1alpha is closely associated with a variety of tumors and oncogenic pathways. Hence, the blocking of HIF-1a itself or HIF-1alpha interacting proteins inhibit tumor growth. Based on these findings, HIF-1 can be a prime target for anticancer therapies. This review summarizes the molecular mechanism of HIF-1a stability, the biological functions of HIF-1 and its potential applications of cancer therapies.
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            Hypoxia-inducible factors and the response to hypoxic stress.

            Oxygen (O(2)) is an essential nutrient that serves as a key substrate in cellular metabolism and bioenergetics. In a variety of physiological and pathological states, organisms encounter insufficient O(2) availability, or hypoxia. In order to cope with this stress, evolutionarily conserved responses are engaged. In mammals, the primary transcriptional response to hypoxic stress is mediated by the hypoxia-inducible factors (HIFs). While canonically regulated by prolyl hydroxylase domain-containing enzymes (PHDs), the HIFα subunits are intricately responsive to numerous other factors, including factor-inhibiting HIF1α (FIH1), sirtuins, and metabolites. These transcription factors function in normal tissue homeostasis and impinge on critical aspects of disease progression and recovery. Insights from basic HIF biology are being translated into pharmaceuticals targeting the HIF pathway. Copyright © 2010 Elsevier Inc. All rights reserved.
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              Intraaortic balloon support for myocardial infarction with cardiogenic shock.

              In current international guidelines, intraaortic balloon counterpulsation is considered to be a class I treatment for cardiogenic shock complicating acute myocardial infarction. However, evidence is based mainly on registry data, and there is a paucity of randomized clinical trials. In this randomized, prospective, open-label, multicenter trial, we randomly assigned 600 patients with cardiogenic shock complicating acute myocardial infarction to intraaortic balloon counterpulsation (IABP group, 301 patients) or no intraaortic balloon counterpulsation (control group, 299 patients). All patients were expected to undergo early revascularization (by means of percutaneous coronary intervention or bypass surgery) and to receive the best available medical therapy. The primary efficacy end point was 30-day all-cause mortality. Safety assessments included major bleeding, peripheral ischemic complications, sepsis, and stroke. A total of 300 patients in the IABP group and 298 in the control group were included in the analysis of the primary end point. At 30 days, 119 patients in the IABP group (39.7%) and 123 patients in the control group (41.3%) had died (relative risk with IABP, 0.96; 95% confidence interval, 0.79 to 1.17; P=0.69). There were no significant differences in secondary end points or in process-of-care measures, including the time to hemodynamic stabilization, the length of stay in the intensive care unit, serum lactate levels, the dose and duration of catecholamine therapy, and renal function. The IABP group and the control group did not differ significantly with respect to the rates of major bleeding (3.3% and 4.4%, respectively; P=0.51), peripheral ischemic complications (4.3% and 3.4%, P=0.53), sepsis (15.7% and 20.5%, P=0.15), and stroke (0.7% and 1.7%, P=0.28). The use of intraaortic balloon counterpulsation did not significantly reduce 30-day mortality in patients with cardiogenic shock complicating acute myocardial infarction for whom an early revascularization strategy was planned. (Funded by the German Research Foundation and others; IABP-SHOCK II ClinicalTrials.gov number, NCT00491036.).
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                Author and article information

                Contributors
                christian.jung@med.uni-duesseldorf.de
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                1 December 2020
                1 December 2020
                2020
                : 10
                Affiliations
                [1 ]GRID grid.21604.31, ISNI 0000 0004 0523 5263, Division of Cardiology, Department of Internal Medicine II, , Paracelsus Medical University of Salzburg, ; Muellner Hauptstrasse 48, 5020 Salzburg, Austria
                [2 ]GRID grid.411327.2, ISNI 0000 0001 2176 9917, Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, , Heinrich-Heine-University, ; Duesseldorf, Germany
                [3 ]GRID grid.7551.6, ISNI 0000 0000 8983 7915, German Aerospace Center (DLR), Institute of Aerospace Medicine, ; Cologne, Germany
                [4 ]GRID grid.411097.a, ISNI 0000 0000 8852 305X, Department of Cardiology, , University Hospital Cologne, ; Cologne, Germany
                [5 ]GRID grid.411327.2, ISNI 0000 0001 2176 9917, Department of Rheumatology, Hiller Research Institute for Rheumatology, Medical Faculty, , Heinrich-Heine-University, ; Duesseldorf, Germany
                [6 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Aeronautics and Astronautics, , Stanford University, ; Stanford, CA 94305 USA
                [7 ]GRID grid.412581.b, ISNI 0000 0000 9024 6397, Department of Anesthesiology and Intensive Care Medicine, Merheim Medical Center, Hospitals of Cologne, , University of Witten/Herdecke, ; Cologne, Germany
                [8 ]GRID grid.6190.e, ISNI 0000 0000 8580 3777, Chair of Aerospace Medicine, Medical Faculty, , University of Cologne, ; Cologne, Germany
                Article
                77724
                10.1038/s41598-020-77724-5
                7708486
                33262355
                7ddf1452-8318-43a6-9414-6da61d860832
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: Projekt DEAL
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                © The Author(s) 2020

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                cardiology, medical research, pathogenesis, hypoxia

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