Publications
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Wiger, Christine Wagle; Ranheim, Trine; Arnesen, Henriette; Vaage, Ingvar Jarle; Pischke, Soeren & Yndestad, Arne
[Show all 8 contributors for this article]
(2025).
TLR4 Inhibition Attenuated LPS-Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes.
Immunity,Inflammation and Disease.
13(1).
doi:
10.1002/iid3.70133.
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Background
Sepsis is associated with myocardial injury and early mortality. The innate immune receptor Toll-like receptor 4 (TLR4) can recognize pathogen-associated-molecular-patterns (PAMPs) and damage-associated molecular patterns (DAMPs); the latter are released during tissue injury. We hypothesized that TLR4 inhibition reduces proinflammatory signaling and cytokine release in: (1) LPS or Escherichia coli-treated isolated mouse heart; (2) LPS-treated mouse primary adult cardiomyocytes; and (3) the isolated heart during ischemia–reperfusion.
Methods
Isolated C57BL/6N male mouse hearts were perfused for 120 min, with either LPS, E. coli, with and without CLI-095 (TLR4 inhibitor). Primary adult mouse cardiomyocytes were treated with LPS or LPS + CLI-095. Isolated hearts, exposed to 35 min of global ischemia, were treated with either vehicle or CLI-095 during reperfusion. Infarct size was quantified by triphenyltetrazolium staining. Cytokine expression was analyzed with ELISA, western blot analysis, and qPCR.
Results
In isolated hearts, E. coli increased the expression of proinflammatory cytokines (IL-6 and CXCL2), which was not attenuated with TLR4 inhibition. TLR4 inhibition reduced expression (p = 0.004) and release of IL-6 (p < 0.0001) in LPS-exposed isolated hearts. LPS activated the nuclear-factor κ-light-chain-enhancer of activated B cells signaling pathway (NF-κB) in primary adult cardiomyocytes. Moreover, TLR4 inhibition reduced LPS-induced mRNA expression and release of IL-6 in primary adult cardiomyocytes. Isolated hearts treated with CLI-095 during reperfusion after ischemia (induced DAMPs release) showed reduced infarct size (39 ± 17% to 26 ± 8%, p = 0.034) and decreased IL-6 release (p = 0.006).
Conclusion
Inhibition of TLR4 reduced proinflammatory signaling and cytokine release in LPS-treated and ischemia–reperfused isolated mouse hearts and in primary adult murine cardiomyocytes.
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Torp, May-Kristin; Stensløkken, Kåre-Olav & Vaage, Ingvar Jarle
(2024).
When Our Best Friend Becomes Our Worst Enemy: The Mitochondrion in Trauma, Surgery, and Critical Illness.
Journal of Intensive Care Medicine.
ISSN 0885-0666.
doi:
10.1177/08850666241237715.
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Zabirnyk, Arsenii; Evensen, Daria; Kvitting, John-Peder; Kaljusto, Mari-Liis; Stensløkken, Kåre-Olav & Vaage, Ingvar Jarle
(2024).
Hyperglycemia-simulating environment attenuated experimentally induced calcification in cultured human aortic valve interstitial cells.
Scandinavian Cardiovascular Journal.
ISSN 1401-7431.
58(1).
doi:
10.1080/14017431.2024.2353070.
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Objectives: The role of diabetes mellitus as a risk factor for the development of calcific aortic valve disease has not been fully clarified. Aortic valve interstitial cells (VICs) have been suggested to be crucial for calcification of the valve. Induced calcification in cultured VICs is a good in vitro model for aortic valve calcification. The purpose of this study was to investigate whether increased glucose levels increase experimentally induced calcification in cultured human VICs. Design: VICs were isolated from explanted calcified aortic valves after valve replacement. Osteogenic medium induced calcification of cultured VICs at different glucose levels (5, 15, and 25 mM). Calcium deposits were visualized using Alizarin Red staining and measured spectrophotometrically. Results: The higher the glucose concentration, the lower the level of calcification. High glucose (25 mM) reduced calcification by 52% compared with calcification at a physiological (5 mM) glucose concentration (correlation and regression analysis: r = −0.55, p = .025 with increased concentration of glucose). Conclusions: In vitro hyperglycemia-like conditions attenuated calcification in VICs. High glucose levels may trigger a series of events that secondarily stimulate calcification of VICs in vivo.
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Aquino, Arthur; Abutalimova, Napisat; Ma, Yi; Ismail-zade, Imran; Grebennik, Vadim & Rubinstein, Artem
[Show all 15 contributors for this article]
(2024).
Differences in Plasma Extracellular Vesicles of Different Origin in On-Pump Versus Off-Pump Cardiac Surgery.
Current Issues in Molecular Biology.
ISSN 1467-3037.
46(11),
p. 13058–13077.
doi:
10.3390/cimb46110779.
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Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) causes a systemic inflammatory response that can worsen patient outcomes. Off-pump surgery has been associated with a reduced inflammatory response. The precise mechanisms and the role of extracellular vesicles (EVs) in this context are not fully understood. This study aimed to investigate the early immune response, including main T- and B-lymphocyte subsets, cytokine profiles, and plasma EVs, in patients undergoing off-pump (n = 18) and on-pump (n = 18) CABG. Thirty-six patients undergoing isolated CABG were enrolled in this randomized control study. Pre- and 24 h postoperative blood samples were analyzed for immune cell populations, cytokine levels, and plasma EV phenotyping. Off-pump CABG triggered a milder immune response than on-pump surgery. On-pump surgery led to greater changes in circulating EVs, particularly platelet- (CD62P+), endothelial- (CD31+), and B-cell-derived (CD19+), as well as platelet- and erythrocyte-derived aggregates (CD41+CD235a+). Levels of platelet-derived EVs, expressing both constitutional and activation markers (CD41+CD62P+) decreased in both groups of patients 24 h after surgery. On-pump cardiac procedures led to an increase in T-regulatory cell-derived EVs (CD73+CD39+), suggesting a potential mechanism for immune suppression compared to off-pump surgery. There were numerous correlations between EV levels and cytokine profiles following on-pump surgery, hinting at a close relationship. Leucocyte-derived EVs exhibited positive correlations with each other and with GRO but showed negative correlations with endothelial-derived EVs (CD90+ and CD31+). Additionally, CD73+ EVs demonstrated positive correlations with platelet counts and with erythrocyte-derived CD235a+ EVs. EV changes were significantly greater after on-pump surgery, highlighting a more pronounced response to this type of surgery and emphasizing the role of EVs as regulators of post-surgical inflammation.
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Chaban, Viktoriia; Boer, Eline de; Ekholt, Karin; Vaage, Ingvar Jarle; Mollnes, Tom Eirik & Nilsson, Per
[Show all 8 contributors for this article]
(2023).
Escherichia coli-induced inflammatory responses are temperature-dependent in human whole blood ex vivo.
Molecular Immunology.
ISSN 0161-5890.
157,
p. 70–77.
doi:
10.1016/j.molimm.2023.03.006.
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Systemic inflammatory conditions are often associated with hypothermia or hyperthermia. Therapeutic hypothermia is used in post-cardiac arrest and some other acute diseases. There is a need for more knowledge concerning the effect of various temperatures on the acute inflammatory response. The complement system plays a crucial role in initiating the inflammatory response. We hypothesized that temperatures above and below the physiologic 37 °C affect complement activation and cytokine production ex vivo. Lepirudin-anticoagulated human whole blood from 10 healthy donors was incubated in the presence or absence of Escherichia coli at different temperatures (4 °C, 12 °C, 20 °C, 33 °C, 37 °C, 39 °C, and 41 °C). Complement activation was assessed by the terminal C5b-9 complement complex (TCC) and the alternative convertase C3bBbP using ELISA. Cytokines were measured using a 27-plex assay. Granulocyte and monocyte activation was evaluated by CD11b surface expression using flow cytometry. A consistent increase in complement activation was observed with rising temperature, reaching a maximum at 41 °C, both in the absence (C3bBbP p < 0.05) and presence (C3bBbP p < 0.05 and TCC p < 0.05) of E. coli. Temperature alone did not affect cytokine production, whereas incubation with E. coli significantly increased cytokine levels of IL-1β, IL-2, IL-6, IL-8, IFN-γ, and TNF at temperatures > 20 °C. Maximum increase occurred at 39 °C. However, a consistent decrease was observed at 41 °C, significant for IL-1β (p = 0.003). Granulocyte CD11b displayed the same temperature-dependent pattern as cytokines, with a corresponding increase in endothelial cell apoptosis and necrosis. Thus, blood temperature differentially determines the degree of complement activation and cytokine release.
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Torp, May-Kristin; Vaage, Ingvar Jarle & Stensløkken, Kåre-Olav
(2023).
Mitochondria-derived damage-associated molecular patterns and inflammation in the ischemic-reperfused heart.
Acta Physiologica.
ISSN 1748-1708.
237(3).
doi:
10.1111/apha.13920.
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Cardiac cell death after myocardial infarction release endogenous structures termed damage-associated molecular patterns (DAMPs) that trigger the innate immune system and initiate a sterile inflammation in the myocardium. Cardiomyocytes are energy demanding cells and 30% of their volume are mitochondria. Mitochondria are evolutionary endosymbionts originating from bacteria containing molecular patterns similar to bacteria, termed mitochondrial DAMPs (mDAMPs). Consequently, mitochondrial debris may be particularly immunogenic and damaging. However, the role of mDAMPs in myocardial infarction is not clarified. Identifying the most harmful mDAMPs and inhibiting their early inflammatory signaling may reduce infarct size and the risk of developing post-infarct heart failure. The focus of this review is the role of mDAMPs in the immediate pro-inflammatory phase after myocardial infarction before arrival of immune cells in the myocardium. We discuss different mDAMPs, their role in physiology and present knowledge regarding their role in the inflammatory response of acute myocardial infarction.
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Semenova, Daria; Zabirnyk, Arsenii; Lobov, Arseniy; Boyarskaya, Nadezda; Kachanova, Olga & Uspensky, Vladimir
[Show all 16 contributors for this article]
(2022).
Multi-omics of in vitro aortic valve calcification.
Frontiers in Cardiovascular Medicine.
9.
doi:
10.3389/fcvm.2022.1043165.
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Heart valve calcification is an active cellular and molecular process that partly remains unknown. Osteogenic differentiation of valve interstitial cells (VIC) is a central mechanism in calcific aortic valve disease (CAVD). Studying mechanisms in CAVD progression is clearly needed. In this study, we compared molecular mechanisms of osteogenic differentiation of human VIC isolated from healthy donors or patients with CAVD by RNA-seq transcriptomics in early timepoint (48 h) and by shotgun proteomics at later timepoint (10th day). Bioinformatic analysis revealed genes and pathways involved in the regulation of VIC osteogenic differentiation. We found a high amount of stage-specific differentially expressed genes and good accordance between transcriptomic and proteomic data. Functional annotation of differentially expressed proteins revealed that osteogenic differentiation of VIC involved many signaling cascades such as: PI3K-Akt, MAPK, Ras, TNF signaling pathways. Wnt, FoxO, and HIF-1 signaling pathways were modulated only at the early timepoint and thus probably involved in the commitment of VIC to osteogenic differentiation. We also observed a significant shift of some metabolic pathways in the early stage of VIC osteogenic differentiation. Lentiviral overexpression of one of the most upregulated genes (ZBTB16, PLZF) increased calcification of VIC after osteogenic stimulation. Analysis with qPCR and shotgun proteomics suggested a proosteogenic role of ZBTB16 in the early stages of osteogenic differentiation.
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Boer, Eline de; Sokolova, Marina; Quach, Huy Quang; Adam, Karin Ekholt Mc; Götz, Maximilian P. & Chaban, Viktoriia
[Show all 13 contributors for this article]
(2022).
Synthetic Oligodeoxynucleotide CpG Motifs Activate Human Complement through Their Backbone Structure and Induce Complement-Dependent Cytokine Release.
Journal of Immunology.
ISSN 0022-1767.
209(9),
p. 1760–1767.
doi:
10.4049/jimmunol.2101191.
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Bacterial and mitochondrial DNA, sharing an evolutionary origin, act as danger-associated molecular patterns in infectious and sterile inflammation. They both contain immunomodulatory CpG motifs. Interactions between CpG motifs and the complement system are sparsely described, and mechanisms of complement activation by CpG remain unclear. Lepirudin-anticoagulated human whole blood and plasma were incubated with increasing concentrations of three classes of synthetic CpGs: CpG-A, -B, and -C oligodeoxynucleotides and their GpC sequence controls. Complement activation products were analyzed by immunoassays. Cytokine levels were determined via 27-plex beads-based immunoassay, and CpG interactions with individual complement proteins were evaluated using magnetic beads coated with CpG-B. In whole blood and plasma, CpG-B and CpG-C (p < 0.05 for both), but not CpG-A (p > 0.8 for all), led to time- and dose-dependent increase of soluble C5b-9, the alternative complement convertase C3bBbP, and the C3 cleavage product C3bc. GpC-A, -B, and -C changed soluble fluid-phase C5b-9, C3bBbP, and C3bc to the same extent as CpG-A, -B, and -C, indicating a DNA backbone–dependent effect. Dose-dependent CpG-B binding was found to C1q (r = 0.83; p = 0.006) and factor H (r = 0.93; p < 0.001). The stimulatory complement effect was partly preserved in C2-deficient plasma and completely preserved in MASP-2–deficient serum. CpG-B increased levels of IL-1β, IL-2, IL-6, IL-8, MCP-1, and TNF in whole blood, which were completely abolished by inhibition of C5 and C5aR1 (p < 0.05 for all). In conclusion, synthetic analogs of bacterial and mitochondrial DNA activate the complement system via the DNA backbone. We suggest that CpG-B interacts directly with classical and alternative pathway components, resulting in complement-C5aR1–dependent cytokine release.
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Torp, May-Kristin; Ranheim, Trine; Schjalm, Camilla; Hjorth, Marit; Heiestad, Christina Mathisen & Dalen, Knut Tomas
[Show all 13 contributors for this article]
(2022).
Intracellular Complement Component 3 Attenuated Ischemia-Reperfusion Injury in the Isolated Buffer-Perfused Mouse Heart and Is Associated With Improved Metabolic Homeostasis.
Frontiers in Immunology.
13.
doi:
10.3389/fimmu.2022.870811.
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The innate immune system is rapidly activated during myocardial infarction and blockade of extracellular complement system reduces infarct size. Intracellular complement, however, appears to be closely linked to metabolic pathways and its role in ischemia-reperfusion injury is unknown and may be different from complement activation in the circulation. The purpose of the present study was to investigate the role of intracellular complement in isolated, retrogradely buffer-perfused hearts and cardiac cells from adult male wild type mice (WT) and from adult male mice with knockout of complement component 3 (C3KO). Main findings: (i) Intracellular C3 protein was expressed in isolated cardiomyocytes and in whole hearts, (ii) after ischemia-reperfusion injury, C3KO hearts had larger infarct size (32 ± 9% in C3KO vs. 22 ± 7% in WT; p=0.008) and impaired post-ischemic relaxation compared to WT hearts, (iii) C3KO cardiomyocytes had lower basal oxidative respiration compared to WT cardiomyocytes, (iv) blocking mTOR decreased Akt phosphorylation in WT, but not in C3KO cardiomyocytes, (v) after ischemia, WT hearts had higher levels of ATP, but lower levels of both reduced and oxidized nicotinamide adenine dinucleotide (NADH and NAD+, respectively) compared to C3KO hearts. Conclusion: intracellular C3 protected the heart against ischemia-reperfusion injury, possibly due to its role in metabolic pathways important for energy production and cell survival.
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Bogdanova, Mariia; Zabirnyk, Arsenii; Malashicheva, Anna; Semenova, Daria; Kvitting, John-Peder & Kaljusto, Mari-Liis
[Show all 12 contributors for this article]
(2022).
Models and Techniques to Study Aortic Valve Calcification in Vitro, ex Vivo and in Vivo. An Overview.
Frontiers in Pharmacology.
13.
doi:
10.3389/fphar.2022.835825.
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Aortic valve stenosis secondary to aortic valve calcification is the most common valve disease in the Western world. Calcification is a result of pathological proliferation and osteogenic differentiation of resident valve interstitial cells. To develop non-surgical treatments, the molecular and cellular mechanisms of pathological calcification must be revealed. In the current overview, we present methods for evaluation of calcification in different ex vivo , in vitro and in vivo situations including imaging in patients. The latter include echocardiography, scanning with computed tomography and magnetic resonance imaging. Particular emphasis is on translational studies of calcific aortic valve stenosis with a special focus on cell culture using human primary cell cultures. Such models are widely used and suitable for screening of drugs against calcification. Animal models are presented, but there is no animal model that faithfully mimics human calcific aortic valve disease. A model of experimentally induced calcification in whole porcine aortic valve leaflets ex vivo is also included. Finally, miscellaneous methods and aspects of aortic valve calcification, such as, for instance, biomarkers are presented.
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Baysa, Anton; Maghazachi, Azzam; Sand, Kristin Larsen; Campesan, Marika; Zaglia, Tania & Mongillo, Marco
[Show all 13 contributors for this article]
(2022).
Toll-like receptor 9 signaling after myocardial infarction: Role of p66ShcA adaptor protein.
Biochemical and Biophysical Research Communications - BBRC.
ISSN 0006-291X.
644,
p. 70–78.
doi:
10.1016/j.bbrc.2022.12.085.
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During myocardial infarction, cellular debris is released, causing a sterile inflammation via pattern recognition receptors. These reactions amplify damage and promotes secondary heart failure. The pattern recognition receptor, Toll-like receptor 9 (TLR9) detects immunogenic fragments of endogenous DNA, inducing inflammation by NFκB. The p66ShcA adaptor protein plays an important role in both ischemic myocardial damage and immune responses. We hypothesized that p66ShcA adaptor protein promotes DNA-sensing signaling via the TLR9 pathway after myocardial infarction. TLR9 protein expression increased in cardiac tissue from patients with end-stage heart failure due to ischemic heart disease. Myocardial ischemia in mice in vivo induced gene expression of key TLR9 pathway proteins (MyD88 and Unc93b1). In this model, a functional link between TLR9 and p66ShcA was revealed as; (i) ischemia-induced upregulation of TLR9 protein was abrogated in myocardium of p66ShcA knockout mice; (ii) when p66ShcA was overexpressed in NFkB reporter cells stably expressing TLR9, NFkB-activation increased during stimulation with the TLR9 agonist CpG B; (iii) in cardiac fibroblasts, p66ShcA overexpression caused TLR9 upregulation. Co-immunoprecipitation showed that ShcA proteins and TLR9 may be found in the same protein complex, which was dissipated upon TLR9 stimulation in vivo. A proximity assay confirmed the co-localization of TLR9 and ShcA proteins. The systemic immune response after myocardial ischemia was dampened in p66ShcA knockout mice as interleukin-4, -17 and −22 expression in mononuclear cells isolated from spleens was reduced. In conclusion, p66ShcA adaptor may be an interaction partner and a regulator of the TLR9 pathway post-infarction.
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Chaban, Viktoriia; Nakstad, Espen R.; Stær-Jensen, Henrik; Schjalm, Camilla; Seljeflot, Ingebjørg & Vaage, Ingvar Jarle
[Show all 12 contributors for this article]
(2021).
Complement activation is associated with poor outcome after out-of-hospital cardiac arrest.
Resuscitation.
ISSN 0300-9572.
166,
p. 129–136.
doi:
10.1016/j.resuscitation.2021.05.038.
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Background Cardiopulmonary resuscitation after cardiac arrest initiates a whole-body ischemia-reperfusion injury, which may activate the innate immune system, including the complement system. We hypothesized that complement activation and subsequent release of soluble endothelial activation markers were associated with cerebral outcome including death. Methods Outcome was assessed at six months and defined by cerebral performance category scale (1−2; good outcome, 3−5; poor outcome including death) in 232 resuscitated out-of-hospital cardiac arrest patients. Plasma samples obtained at admission and day three were analysed for complement activation products C3bc, the soluble terminal complement complex (sC5b-9), and soluble CD14. Endothelial cell activation was measured by soluble markers syndecan-1, sE-selectin, thrombomodulin, and vascular cell adhesion molecule. Results Forty-nine percent of the patients had good outcome. C3bc and sC5b-9 were significantly higher at admission compared to day three (p < 0.001 for both) and in patients with poor compared to good outcome (p = 0.03 and p < 0.001, respectively). Unadjusted, higher sC5b-9 at admission was associated with poor outcome (odds ratio 1.08 (95% CI 1.01–1.14), p = 0.024). Adjusted, sC5b-9 was still associated with outcome, but the association became non-significant when time to return-of-spontaneous-circulation above 25 min was included as a covariate. Endothelial cell activation markers increased from admission to day three, but only sE-selectin and thrombomodulin were significantly higher in patients with poor versus good outcome (p = 0.004 and p = 0.03, respectively) and correlated to sCD14 and sC5b-9/C3bc, respectively. Conclusion Complement system activation, reflected by sC5b-9 at admission, leading to subsequent endothelial cell activation, was associated with poor outcome in out-of-hospital cardiac arrest patients.
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Li, Yuchuan; Khanal, Prabhat; Norheim, Frode; Hjorth, Marit; Bjellaas, Thomas & Drevon, Christian A
[Show all 9 contributors for this article]
(2021).
Plin2 deletion increases cholesteryl ester lipid droplet content and disturbs cholesterol balance in adrenal cortex.
Journal of Lipid Research.
ISSN 0022-2275.
62.
doi:
10.1016/J.JLR.2021.100048.
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Cholesteryl esters (CEs) are the water-insoluble transport and storage form of cholesterol. Steroidogenic cells primarily store CEs in cytoplasmic lipid droplet (LD) organelles, as contrasted to the majority of mammalian cell types that predominantly store triacylglycerol (TAG) in LDs. The LD-binding Plin2 binds to both CE- and TAG-rich LDs, and although Plin2 is known to regulate degradation of TAG-rich LDs, its role for regulation of CE-rich LDs is unclear. To investigate the role of Plin2 in the regulation of CE-rich LDs, we performed histological and molecular characterization of adrenal glands from Plin2+/+ and Plin2−/− mice. Adrenal glands of Plin2−/− mice had significantly enlarged organ size, increased size and numbers of CE-rich LDs in cortical cells, elevated cellular unesterified cholesterol levels, and increased expression of macrophage markers and genes facilitating reverse cholesterol transport. Despite altered LD storage, mobilization of adrenal LDs and secretion of corticosterone induced by adrenocorticotropic hormone stimulation or starvation were similar in Plin2+/+ and Plin2−/− mice. Plin2−/− adrenals accumulated ceroid-like structures rich in multilamellar bodies in the adrenal cortex-medulla boundary, which increased with age, particularly in females. Finally, Plin2−/− mice displayed unexpectedly high levels of phosphatidylglycerols, which directly paralleled the accumulation of these ceroid-like structures. Our findings demonstrate an important role of Plin2 for regulation of CE-rich LDs and cellular cholesterol balance in the adrenal cortex.
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Arain, Fizza Kanwal; Abraityte, Judita Aurelija; Bogdanova, Mariia; Solberg, Ole Geir; Michelsen, Annika & Lekva, Tove
[Show all 19 contributors for this article]
(2020).
YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis.
Circulation: Heart Failure.
ISSN 1941-3289.
13(10),
p. e006643–e006643.
doi:
10.1161/CIRCHEARTFAILURE.119.006643.
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BACKGROUND: Identification of novel biomarkers could provide prognostic information and improve risk stratification in patients with aortic stenosis (AS). YKL-40 (chitinase-3-like protein 1), a protein involved in atherogenesis, is upregulated in human calcific aortic valves. We hypothesized that circulating YKL-40 would be elevated and associated with the degree of AS severity and outcome in patients with symptomatic AS. METHODS: Plasma YKL-40 was analyzed in 2 AS populations, one severe AS (n=572) with outcome measures and one with mixed severity (n=67). YKL-40 expression in calcified valves and in an experimental pressure overload model was assessed. RESULTS: We found (1) patients with AS had upregulated circulating YKL-40 compared with healthy controls (median 109 versus 34 ng/mL, P<0.001), but levels were not related to the degree of AS severity. (2) High YKL-40 levels (quartile 4) were associated with long-term (median follow-up 4.7 years) all-cause mortality (adjusted hazard ratio, 1.93 [95% CI, 1.37–2.73], P<0.001). (3) YKL-40 protein expression in human calcific valves co-localized with its putative receptor IL-13rα2 in close proximity to valve interstitial cells. (4) Myocardial YKL-40 increased in experimental pressure overload (6-fold in decompensated versus sham mice). CONCLUSIONS: YKL-40 levels were elevated in AS and associated with mortality but not with other metrics of disease severity including the degree of AS severity. Despite scientific rationale for its role in AS, the clinical utility of circulating YKL-40 as a biomarker is limited.
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Li, Yuchuan; Torp, May-Kristin; Norheim, Frode; Khanal, Prabhat; Kimmel, Alan R. & Stensløkken, Kåre-Olav
[Show all 8 contributors for this article]
(2020).
Isolated Plin5-deficient cardiomyocytes store less lipid droplets than normal, but without increased sensitivity to hypoxia.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids.
ISSN 1388-1981.
1866(4).
doi:
10.1016/j.bbalip.2020.158873.
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Plin5 is abundantly expressed in the heart where it binds to lipid droplets (LDs) and facilitates physical interaction between LDs and mitochondria. We isolated cardiomyocytes from adult Plin5+/+ and Plin5-/- mice to study the role of Plin5 for fatty acid uptake, LD accumulation, fatty acid oxidation, and tolerance to hypoxia. Cardiomyocytes isolated from Plin5-/- mice cultured with oleic acid stored less LDs than Plin5+/+, but comparable levels to Plin5+/+ cardiomyocytes when adipose triglyceride lipase activity was inhibited. The ability to oxidize fatty acids into CO2 was similar between Plin5+/+ and Plin5-/- cardiomyocytes, but Plin5-/- cardiomyocytes had a transient increase in intracellular fatty acid oxidation intermediates. After pre-incubation with oleic acids, Plin5-/- cardiomyocytes retained a higher content of glycogen and showed improved tolerance to hypoxia compared to Plin5+/+. In isolated, perfused hearts, deletion of Plin5 had no important effect on ventricular pressures or infarct size after ischemia. Old Plin5-/- mice had reduced levels of cardiac triacylglycerides, increased heart weight, and apart from modest elevated expression of mRNAs for beta myosin heavy chain Myh7 and the fatty acid transporter Cd36, other genes involved in fatty acid oxidation, glycogen metabolism and glucose utilization were essentially unchanged by removal of Plin5. Plin5 seems to facilitate cardiac LD storage primarily by repressing adipose triglyceride lipase activity without altering cardiac fatty acid oxidation capacity. Expression of Plin5 and cardiac LD content of isolated cardiomyocytes has little importance for tolerance to acute hypoxia and ischemia, which contrasts the protective role for Plin5 in mouse models during myocardial ischemia.
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Zabirnyk, Arsenii; Perez, Maria del Mar; Blasco, Marc; Stensløkken, Kåre-Olav; Ferrer, Miguel D. & Salcedo, Carolina
[Show all 7 contributors for this article]
(2020).
A Novel Ex Vivo Model of Aortic Valve Calcification. A Preliminary Report.
Frontiers in Pharmacology.
11.
doi:
10.3389/fphar.2020.568764.
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Background: No pharmacological treatment exists to prevent or stop the calcification process of aortic valves causing aortic stenosis. The aim of this study was to develop a robust model of induced calcification in whole aortic valve leaflets which could be suitable for studies of the basic mechanisms and for testing potentially inhibitory drugs. Methods: Pig hearts were obtained from a commercial abattoir. The aortic valve leaflets were dissected free and randomized between experimental groups. Whole leaflets were cultured in individual wells. Two growth media were used for cultivation: standard growth medium and an antimyofibroblastic growth medium. The latter was employed to inhibit contraction of the leaflet into a ball-like structure. Calcification was induced in the growth medium by supplementation with an osteogenic medium. Leaflets were cultivated for four weeks and medium was changed every third day. To block calcification, the inhibitor SNF472 (a formulation of the hexasodium salt of myo-inositol hexaphosphate hexasodium salt) was used at concentrations between 1 and 100 µM. After cultivation for four weeks the leaflets were snap frozen in liquid nitrogen and kept at −80 °C until blind assessment of the calcium amount in leaflets by inductively coupled plasma optical emission spectroscopy. For statistical analysis, a Kruskal–Wallis test with Dunn’s post-test was applied. Results: Osteodifferentiation with calcium accumulation was in principle absent when standard medium was used. However, when the antimyofibroblastic medium was used, a strong calcium accumulation was induced ( p = 0.006 compared to controls), and this was blocked in a dose-dependent manner by the calcification inhibitor SNF472 ( p = 0.008), with an EC 50 of 3.3 µM. Conclusion: A model of experimentally induced calcification in cultured whole leaflets from porcine aortic valves was developed. This model can be useful for studying the basic mechanisms of valve calcification and to test pharmacological approaches to inhibit calcification.
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Zabirnyk, Arsenii; Ferrer, Miguel David; Bogdanova, Mariia; Perez, MM; Salcedo, C & Kaljusto, Mari-Liis
[Show all 10 contributors for this article]
(2019).
SNF472, a novel anti-crystallization agent, inhibits induced calcification in an in vitro model of human aortic valve calcification.
Vascular pharmacology.
ISSN 1537-1891.
p. 1–7.
doi:
10.1016/j.vph.2019.106583.
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The purpose of the present study was to investigate whether SNF472, the hexasodium salt of myo-inositol hexaphosphate (IP6 or phytate): 1. Inhibits induced calcification in cultured aortic valve interstitial cells (VIC) as an in vitro model of aortic valve stenosis and 2. Whether inhibition is different in VIC obtained from healthy and calcified aortic valves. VIC from healthy (n = 5) and calcified (n = 7) human aortic valves were seeded in basic growth medium, osteogenic differentiation medium alone, or in osteogenic medium with SNF472 (3, 10, and 30 μM) and cultivated for 3 weeks. Calcification was quantified spectrophotometrically after Alizarin Red staining. In VIC from calcified valves, a complete inhibition of calcification was observed with SNF472 concentrations of 10 and 30 μM (p < .01), significantly stronger than in VIC from healthy valves. When SNF472 was added to VIC after 1 week in osteogenic medium, 30 and 100 μM SNF472 inhibited the progression of ongoing calcification by 81 and 100% (p < .01), respectively. The same concentrations of SNF472 given after 2 weeks reduced calcification by 35 and 40% respectively (not significant). SNF472 inhibited both the formation and the progression of calcification with the strongest effect in VIC from calcified valves.
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Mariero, Lars Henrik; Torp, May-Kristin; Heiestad, Christina Mathisen; Baysa, Anton; Li, Yuchuan & Valen, Guro
[Show all 8 contributors for this article]
(2019).
Inhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation.
British Journal of Pharmacology.
ISSN 0007-1188.
176(22),
p. 4360–4372.
doi:
10.1111/bph.14830.
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Background and purpose Cellular debris causes sterile inflammation after myocardial infarction. Mitochondria constitute about 30 percent of the human heart. Mitochondrial DNA (mtDNA) is a damage‐associated‐molecular‐pattern that induce injurious sterile inflammation. Little is known about mtDNA's inflammatory signalling pathways in cardiomyocytes and how mtDNA is internalized to associate with its putative receptor, toll‐like receptor 9 (TLR9). Experimental Approach We hypothesized that mtDNA can be internalized in cardiomyocytes and induce an inflammatory response. Adult mouse cardiomyocytes were exposed to hypoxia‐reoxygenation and extracellular DNA. Microscale thermophoresis was used to demonstrate binding between nucleolin and DNA. Key results Expression of the pro‐inflammatory cytokines IL‐1β and TNFα were upregulated by mtDNA, but not by nuclear DNA (nDNA), in cardiomyocytes exposed to hypoxia‐reoxygenation. Blocking the RNA/DNA binding protein nucleolin with midkine reduced expression of IL‐1β/TNFα and the nucleolin inhibitor AS1411 reduced interleukin‐6 release in adult mouse cardiomyocytes. mtDNA bound 10‐fold stronger than nDNA to nucleolin. In HEK293‐NF‐κB reporter cells, mtDNA induced NF‐κB activity in normoxia, while CpG‐DNA and hypoxia‐reoxygenation, synergistically induced TLR9‐dependent NF‐κB activity. Protein expression of nucleolin was found in the plasma membrane of cardiomyocytes and inhibition of nucleolin with midkine inhibited cellular uptake of CpG‐DNA. Inhibition of endocytosis did not reduce CpG‐DNA uptake in cardiomyocytes. Conclusion and implications mtDNA, but not nDNA, induce an inflammatory response in mouse cardiomyocytes during hypoxia‐reoxygenation. In cardiomyocytes, nucleolin is expressed on the membrane and blocking nucleolin reduce inflammation. Nucleolin might be a therapeutic target to prevent uptake of immunogenic DNA and reduce inflammation.
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Bogdanova, Mariia; Zabirnyk, Arsenii; Malashicheva, Anna; Zihlavnikova, Katarina; Karlsen, Tommy Aleksander & Kaljusto, Mari-Liis
[Show all 13 contributors for this article]
(2019).
Interstitial cells in calcified aortic valves have reduced differentiation potential and stem cell-like properties.
Scientific Reports.
9:12934,
p. 1–13.
doi:
10.1038/s41598-019-49016-0.
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Valve interstitial cells (VICs) are crucial in the development of calcific aortic valve disease. The purpose of the present investigation was to compare the phenotype, differentiation potential and stem cell-like properties of cells from calcified and healthy aortic valves. VICs were isolated from human healthy and calcified aortic valves. Calcification was induced with osteogenic medium. Unlike VICs from healthy valves, VICs from calcified valves cultured without osteogenic medium stained positively for calcium deposits with Alizarin Red confirming their calcific phenotype. Stimulation of VICs from calcified valves with osteogenic medium increased calcification (p = 0.02), but not significantly different from healthy VICs. When stimulated with myofibroblastic medium, VICs from calcified valves had lower expression of myofibroblastic markers, measured by flow cytometry and RT-qPCR, compared to healthy VICs. Contraction of collagen gel (a measure of myofibroblastic activity) was attenuated in cells from calcified valves (p = 0.04). Moreover, VICs from calcified valves, unlike cells from healthy valves had lower potential to differentiate into adipogenic pathway and lower expression of stem cell-associated markers CD106 (p = 0.04) and aldehyde dehydrogenase (p = 0.04). In conclusion, VICs from calcified aortic have reduced multipotency compared to cells from healthy valves, which should be considered when investigating possible medical treatments of aortic valve calcification.
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Kimose, Hans-Henrik; Randsbæk, Flemming; Christensen, Thomas Decker; Valen, Guro; Bøtker, Hans Erik & Vaage, Ingvar Jarle
(2018).
A dose-response study of glutamate supplementation in isolated, perfused rat hearts undergoing ischaemia and cold cardioplegia.
European Journal of Cardio-Thoracic Surgery.
ISSN 1010-7940.
53(3),
p. 664–671.
doi:
10.1093/ejcts/ezx368.
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Bogdanova, Mariia; Kostina, Aleksandra; Zihlavnikova, Katarina; Zabirnyk, Arsenii; Malashicheva, Anna & Stensløkken, Kåre-Olav
[Show all 12 contributors for this article]
(2018).
Inflammation and Mechanical Stress Stimulate Osteogenic Differentiation of Human Aortic Valve Interstitial Cells.
Frontiers in Physiology.
9.
doi:
10.3389/fphys.2018.01635.
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Background: Aortic valve calcification is an active proliferative process, where interstitial cells of the valve transform into either myofibroblasts or osteoblast-like cells causing valve deformation, thickening of cusps and finally stenosis. This process may be triggered by several factors including inflammation, mechanical stress or interaction of cells with certain components of extracellular matrix. The matrix is different on the two sides of the valve leaflets. We hypothesize that inflammation and mechanical stress stimulate osteogenic differentiation of human aortic valve interstitial cells (VICs) and this may depend on the side of the leaflet. Methods: Interstitial cells isolated from healthy and calcified human aortic valves were cultured on collagen or elastin coated plates with flexible bottoms, simulating the matrix on the aortic and ventricular side of the valve leaflets, respectively. The cells were subjected to 10% stretch at 1 Hz (FlexCell bioreactor) or treated with 0.1 μg/ml lipopolysaccharide, or both during 24 h. Gene expression of myofibroblast- and osteoblast-specific genes was analyzed by qPCR. VICs cultured in presence of osteogenic medium together with lipopolysaccharide, 10% stretch or both for 14 days were stained for calcification using Alizarin Red. Results: Treatment with lipopolysaccharide increased expression of osteogenic gene bone morphogenetic protein 2 (BMP2) (5-fold increase from control; p = 0.02) and decreased expression of mRNA of myofibroblastic markers: α-smooth muscle actin (ACTA2) (50% reduction from control; p = 0.0006) and calponin (CNN1) (80% reduction from control; p = 0.0001) when cells from calcified valves were cultured on collagen, but not on elastin. Mechanical stretch of VICs cultured on collagen augmented the effect of lipopolysaccharide. Expression of periostin (POSTN) was inhibited in cells from calcified donors after treatment with lipopolysaccharide on collagen (70% reduction from control, p = 0.001), but not on elastin. Lipopolysaccharide and stretch both enhanced the pro-calcific effect of osteogenic medium, further increasing the effect when combined for cells cultured on collagen, but not on elastin. Conclusion: Inflammation and mechanical stress trigger expression of osteogenic genes in VICs in a side-specific manner, while inhibiting the myofibroblastic pathway. Stretch and lipopolysaccharide synergistically increase calcification.
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Rutkovskiy, Arkady; Malashicheva, Anna; Sullivan, Gareth; Bogdanova, Mariia; Kostareva, Anna & Stensløkken, Kåre-Olav
[Show all 8 contributors for this article]
(2017).
Valve interstitial cells: The key to understanding the pathophysiology of heart valve calcification.
Journal of the American Heart Association (JAHA).
6(9),
p. 1–24.
doi:
10.1161/JAHA.117.006339.
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Aortic valve stenosis due to calcification of the valve leaflets is the most common valve disease in the developed world. It is the third leading cause of cardiovascular disease.1 Risk factors include male gender, smoking, diabetes mellitus, hypertension, high levels of circulating lipids, and metabolic syndrome.2 Calcification was earlier believed to be a passive degenerative process, but it is now recognized as an active disease process driven by the cells native to the aortic valve.3, 4 The only option for treatment is heart surgery with implantation of a valve prosthesis. The heart valve prostheses are either mechanical, requiring life‐long anticoagulation treatment, or based on biological material, which will degenerate and calcify after 10 to 15 years. Implantation of heart valve prostheses has been characterized as “replacing one disease with another.” Understanding the cellular and molecular processes behind valve calcification may possibly lead to nonsurgical treatment.
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Bliksøen, Marte; Rutkovskiy, Arkady; Vaage, Ingvar Jarle & Stensløkken, Kåre-Olav
(2017).
Mode of perfusion influences infarct size, coronary flow and stress kinases in the isolated mouse heart.
Acta Physiologica.
ISSN 1748-1708.
220(1),
p. 36–46.
doi:
10.1111/apha.12773.
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Aim: The isolated, retrogradely perfused heart (modified Langendorff
model) is a widely used method in experimental heart research. The presence
of an intraventricular balloon is necessary to get functional measurements.
We have previously shown that the balloon induces
phosphorylation of some suggested cardioprotective mitogen-activated protein
kinases (MAPK): P38-MAPK, ERK 1/2 and JNK. We hypothesized
that the balloon could influence cardioprotection, protect against ischaemia
reperfusion injury and interfere with coronary flow.
Methods and Results: Isolated mouse hearts were perfused for 5, 10, 20,
40 and 60 min with a balloon in the left ventricle. We found a wavelike
phosphorylation of all MAPK while AKT displayed a gradual dephosphorylation
when compared to non-perfused hearts. Hearts were subjected to
20 min of stabilization with or without the balloon, followed by 35 min of
ischaemia and 120 min of reperfusion. Although the MAPK were phosphorylated,
the infarcts were larger in the balloon group. When the balloon
was present during the entire protocol, compared to removal at the end of
ischaemia, the infarct size was also larger, especially in the endocardial
layer. The balloon reduced post-ischaemic endocardial coronary flow,
despite a higher average flow, indicating a hyperperfused epicard. Blocking
the balloon-induced ERK 1/2 phosphorylation during stabilization did not
affect infarct size. The effect of post-conditioning was influenced by the
balloon, showing reduced infarct size when the balloon was present.
Conclusion: The balloon used for pressure measurements may contributes
to cell death possibly by reducing endocardial coronary flow.
Keywords coronary flow, kinases, Langendorff, perfusion, post-conditioning,
pre-conditioning.
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Reine, Trine M.; Vuong, Tram Thu; Rutkovskiy, Arkady; Meen, Astri Jeanette; Vaage, Ingvar Jarle & Jenssen, Trond Geir
[Show all 7 contributors for this article]
(2015).
Serglycin in Quiescent and Proliferating
Primary Endothelial Cells.
PLOS ONE.
10(12).
doi:
10.1371/journal.pone.0145584.
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Proteoglycans are fundamental components of the endothelial barrier, but the functions of the proteoglycan serglycin in endothelium are less described. Our aim was to describe the roles of serglycin in processes relevant for endothelial dysfunction. Primary human umbilical vein endothelial cells (HUVEC) were cultured in vitro and the expression of proteoglycans was investigated. Dense cell cultures representing the quiescent endothelium coating the vasculature was compared to sparse activated cell cultures, relevant for diabetes, cancer and cardiovascular disease. Secretion of 35S- proteoglycans increased in sparse cultures, and we showed that serglycin is a major component of the cell-density sensitive proteoglycan population. In contrast to the other proteoglycans, serglycin expression and secretion was higher in proliferating compared to quiescent HUVEC. RNAi silencing of serglycin inhibited proliferation and wound healing, and serglycin expression and secretion was augmented by hypoxia, mechanical strain and IL-1β induced inflammation. Notably, the secretion of the angiogenic chemokine CCL2 resulting from IL-1β activation, was increased in serglycin knockdown cells, while angiopoietin was not affected. Both serglycin and CCL2 were secreted predominantly to the apical side of polarized HUVEC, and serglycin and CCL2 co-localized both in perinuclear areas and in vesicles. These results suggest functions for serglycin in endothelial cells trough interactions with partner molecules, in biological processes with relevance for diabetic complications, cardiovascular disease and cancer development.
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Nilsson, Göran Erik; Vaage, Ingvar Jarle & Stensløkken, Kåre-Olav
(2015).
Oxygen- and temperature-dependent expression of survival protein kinases in crucian carp (carassius carassius) heart and brain.
American Journal of Physiology. Regulatory Integrative and Comparative Physiology.
ISSN 0363-6119.
308(1),
p. R50–R61.
doi:
10.1152/ajpregu.00094.2014.
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Rutkovskiy, Arkady; Mariero, Lars Henrik & Vaage, Ingvar Jarle
(2014).
Deletion of the aquaporin-4 gene alters expression and phosphorylation of protective kinases in the mouse heart.
Scandinavian Journal of Clinical and Laboratory Investigation.
ISSN 0036-5513.
74(6),
p. 500–505.
doi:
10.3109/00365513.2014.905698.
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Stensløkken, Kåre-Olav; Ellefsen, Stian; Vasieva, Olga; Fang, Youhan; Farrell, Anthony P. & Olohan, Lisa
[Show all 9 contributors for this article]
(2014).
Life without Oxygen: Gene Regulatory Responses of the Crucian Carp (Carassius carassius) Heart Subjected to Chronic Anoxia.
PLOS ONE.
9(11).
doi:
10.1371/journal.pone.0109978.
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Crucian carp are unusual among vertebrates in surviving extended periods in the complete absence of molecular oxygen. During this time cardiac output is maintained though these mechanisms are not well understood. Using a high-density cDNA microarray, we have defined the genome-wide gene expression responses of cardiac tissue after exposing the fish at two temperatures (8 and 13uC) to one and seven days of anoxia, followed by seven days after restoration to normoxia. At 8uC, using a false discovery rate of 5%, neither anoxia nor re-oxygenation elicited appreciable changes in gene expression. By contrast, at 13uC, 777 unique genes responded strongly. Up-regulated genes included those involved in protein turnover, the pentose phosphate pathway and cell morphogenesis while down-regulated gene categories included RNA splicing and transcription. Most genes were affected between one and seven days of anoxia, indicating gene regulation over the medium term but with few early response genes. Re-oxygenation for 7 days was sufficient to completely reverse these responses. Glycolysis displayed more complex responses with anoxia up-regulated transcripts for the key regulatory enzymes, hexokinase and phosphofructokinase, but with down-regulation of most of the non-regulatory genes. This complex pattern of responses in genomic transcription patterns indicates divergent cardiac responses to anoxia, with the transcriptionally driven reprogramming of cardiac function seen at 13uC being largely completed at 8uC.
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Mariero, Lars Henrik; Rutkovskiy, Arkady; Stensløkken, Kåre-Olav & Vaage, Ingvar Jarle
(2012).
Hyperoxia during early reperfusion does not increase ischemia-reperfusion injury.
European Journal of Cardio-Thoracic Surgery.
ISSN 1010-7940.
41(1),
p. 149–153.
doi:
10.1016/j.ejcts.2011.04.022.
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Troitskaya, Maria P.; Baysa, Anton; Vaage, Ingvar Jarle; Sand, Kristin Larsen; Maghazachi, Azzam & Valen, Guro
(2012).
IL-17 level is reduced during acute myocardial infarction. Role of chemokine receptor expression in monocytes and their in vitro chemotaxis towards chemokines.
Toxins.
4(12),
p. 1427–1439.
doi:
10.3390/toxins4121427.
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Rutkovskiy, Arkady; Mariero, Lars Henrik; Nygård, Ståle; Stensløkken, Kåre-Olav; Valen, Guro & Vaage, Ingvar Jarle
(2012).
Transient hyperosmolality modulates expression of cardiac aquaporins.
Biochemical and Biophysical Research Communications - BBRC.
ISSN 0006-291X.
425(1),
p. 70–75.
doi:
10.1016/j.bbrc.2012.07.052.
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Stensløkken, Kåre-Olav; Ellefsen, Stian; Larsen, Helene Kile; Vaage, Ingvar Jarle & Nilsson, Göran Erik
(2010).
Expression of heat shock proteins in anoxic crucian carp (Carassius carassius): support for cold as a preparatory cue for anoxia.
American Journal of Physiology. Regulatory Integrative and Comparative Physiology.
ISSN 0363-6119.
298(6),
p. R1499–R1508.
doi:
10.1152/ajpregu.00675.2009.
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Kaljusto, Mari-Liis; Rutkovskiy, Arkady; Stensløkken, Kåre-Olav & Vaage, Ingvar Jarle
(2010).
Postconditioning in mouse hearts is inhibited by blocking the reverse mode of the sodium - calcium exchanger.
Interactive Cardiovascular and Thoracic Surgery.
ISSN 1569-9293.
10,
p. 743–748.
doi:
10.1510/icvts.2009.217083.
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Stensløkken, Kåre-Olav; Rutkovskiy, Arkady; Kaljusto, Mari-Liis; Hafstad, Anne Dragøy; Larsen, Terje Steinar & Vaage, Ingvar Jarle
(2009).
Inadvertent phosphorylation of survival kinases in isolated perfused hearts: a word of caution.
Basic Research in Cardiology.
ISSN 0300-8428.
104,
p. 412–423.
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Chen, F; Eriksson, P; Whatling, C; Vaage, Ingvar Jarle & Valen, Guro
(2008).
Surgical handling of saphenous vein grafts induces expression of matrix metalloproteinase 9.
Scandinavian Cardiovascular Journal.
ISSN 1401-7431.
42,
p. 327–336.
doi:
10.1080/14017430801919540.
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Bliksøen, Marte; Kaljusto, Mari-Liis; Vaage, Ingvar Jarle & Stensløkken, Kåre-Olav
(2008).
Effects of hydrogen sulphide on ischaemia-reperfusion injury and ischaemic preconditioning in the isolated, perfused rat heart.
European Journal of Cardio-Thoracic Surgery.
ISSN 1010-7940.
34,
p. 344–349.
doi:
10.1016/j.ejcts.2008.03.017.
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Labruto, F; Song, XL; Valen, Guro & Vaage, Ingvar Jarle
(2006).
Lazaroid U-83836E improves tolerance to hemorrhagic shock and limb ischemia and reperfusion in rats and increases cardiac heat shock protein 72.
Academic Emergency Medicine (AEM).
ISSN 1069-6563.
13,
p. 7–12.
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Valen, Guro & Vaage, Ingvar Jarle
(2005).
The role of tumor necrosis factor alpha and its receptor 1 in preconditioning by hyperoxia.
Basic Research in Cardiology.
ISSN 0300-8428.
100,
p. 198–207.
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Valen, Guro & Vaage, Ingvar Jarle
(2005).
Pre- and postconditioning during cardiac surgery.
Basic Research in Cardiology.
ISSN 0300-8428.
100,
p. 179–186.
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Valen, Guro & Vaage, Ingvar Jarle
(2005).
Intraperitoneal injections of fluid adapts the mouse heart to ischemia.
Laboratory Animals.
ISSN 0023-6772.
39,
p. 298–307.
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Valen, Guro & Vaage, Ingvar Jarle
(2004).
Brief global ischemia converts persistant reperfusion-induced ventricular fibrillation into regular rhythm in the rat heart.
Interactive Cardiovascular and Thoracic Surgery.
ISSN 1569-9293.
25,
p. 1006–1010.
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Valen, Guro & Vaage, Ingvar Jarle
(2004).
Myocardial protection by remote preconditioning: The role of nuclear factor kappa B p105 and inducible nitric oxide synthase.
European Journal of Cardio-Thoracic Surgery.
ISSN 1010-7940.
26,
p. 968–973.
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Valen, Guro & Vaage, Ingvar Jarle
(2004).
Metabolic changes induced by ischemia and cardioplegia: A study employing microdialysis in pigs on cardiopulmonary bypass.
European Journal of Cardio-Thoracic Surgery.
ISSN 1010-7940.
25,
p. 69–75.
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Mariero, Lars Henrik; Rutkovskiy, Arkady; Stensløkken, Kåre-Olav & Vaage, Ingvar Jarle
(2010).
May hyperoxic ventilation during early reperfusion increase infarct size?
Cardiovascular Research (CVR).
ISSN 0008-6363.
87,
p. S134–S134.
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Bliksoen, M; Rutkovskiy, Arkady; Mariero, Lars Henrik; Vaage, Ingvar Jarle & Stensløkken, Kåre-Olav
(2010).
Phosphorylation of survival kinases is not a guarantee for protection of ischemia-reperfusion injury in the isolated, perfused mouse heart.
Cardiovascular Research (CVR).
ISSN 0008-6363.
87,
p. S85–S85.
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Rutkovskiy, Arkady; Mariero, Lars Henrik; Stensløkken, Kåre-Olav; Valen, Guro & Vaage, Ingvar Jarle
(2010).
Osmotic pressure regulates expression levels of cardiac aquaporins 1 and 4.
Cardiovascular Research (CVR).
ISSN 0008-6363.
87,
p. S104–S104.
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Manne, Per Erik; Lode, Beate; Thorsen, Kirsten; Vaage, Ingvar Jarle; Johnsen, Kari Bjørgo & Helgesen, Carsten Gunnar
[Show all 11 contributors for this article]
(2015).
Retningslinjer for karakterskalaen bestått/ikke beståttRapport fra en arbeidsgruppe oppnevnt av Utdanningsutvalget i UHRNovember 2015.
Universitets- og Høgskolerådet/The Norwegian Association of Higher Education Institutions.
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Published
Apr. 13, 2011 2:54 PM
- Last modified
May 27, 2011 4:05 PM
