Arne Olav Melleby

• Veras, Ioanni; Eken, Olav Søvik; Levy, Finn Olav; Melleby, Arne Olav & Aronsen, Jan Magnus (2026). Protocol for isolation of nuclei from murine cardiac tissue for single-nucleus multiomic sequencing. STAR Protocols. 7(2). doi: 10.1016/j.xpro.2026.104615. Full text in Research Archive
• Hauge-Iversen, Ida Marie; Nordén, Einar Sjaastad; Melleby, Arne Olav; Zhang, Lili; Sjaastad, Ivar & Espe, Emil Knut Stenersen (2025). Longitudinal cardiovascular magnetic resonance evaluation of progressive pressure overload due to O-ring induced ascending aortic constriction in rats. Journal of Cardiovascular Magnetic Resonance. ISSN 1097-6647. 27(2). doi: 10.1016/j.jocmr.2025.101969. Full text in Research Archive Show summary

  Background Aortic stenosis is a debilitating disease characterized by pressure overload and development of myocardial fibrosis. Animal models that mimic this disease are crucial for translational research. Aortic constriction in rats is commonly used to induce pressure overload, but the precise disease progression in the O-ring induced model of ascending aortic constriction has not been thoroughly evaluated. Additionally, identifying early imaging biomarkers that can predict fibrosis could enhance the model’s translational relevance. This study aims to evaluate a rat model of progressive pressure overload using cardiovascular magnetic resonance imaging (CMR) by investigating the degree of constriction at different time points and identifying early imaging biomarkers predicting myocardial fibrosis at later stages. Methods Sprague Dawley rats (n=14) underwent aortic banding with O-rings (inner diameter of 1.5 mm or 1.3 mm). Sham-operated rats (n=8) served as controls. CMR was performed every fourth week until 20 weeks post-surgery, followed by tissue harvesting and measurements of fibrosis with histology. Results All banding groups gradually developed left ventricular (LV) hypertrophy, impaired LV diastolic function (increased E/SRe), increased left atrial (LA) size, and impaired LA function (reduced LA ejection fraction and peak LA strain), but preserved LV ejection fraction during the course of study. The tightest constriction exhibited increased LV fibrosis at 20 weeks. LA diameter at 4 weeks independently predicted LV myocardial fibrosis. Conclusion This animal model mimics the gradual progression of stenosis seen in humans, highlighting its translational potential. Early LA diameter predicted myocardial fibrosis. These findings underscore the model’s relevance for studying disease progression in LV pressure overload.

• Hauge-Iversen, Ida Marie; Nordén, Einar Sjaastad; Melleby, Arne Olav; Espeland, Linn Stordahl; Zhang, Lili & Sjaastad, Ivar [Show all 7 contributors for this article] (2025). Non-invasive estimation of left ventricular chamber stiffness using cardiovascular magnetic resonance and echocardiography. Journal of Cardiovascular Magnetic Resonance. ISSN 1097-6647. 27(1). doi: 10.1016/j.jocmr.2025.101849. Full text in Research Archive Show summary

  Background Preclinical studies exploring the underlying mechanisms of elevated left ventricular (LV) chamber stiffness play a crucial role in developing new therapeutic strategies. However, there is a lack of systematic evaluation of imaging biomarkers of diastolic function against gold standard assessment of LV chamber stiffness in rodents. Therefore, we aimed to evaluate imaging biomarkers of diastolic function from cardiovascular magnetic resonance (CMR) and echocardiography in predicting the slope of the end-diastolic pressure-volume relationship (EDPVR) in rats. Methods Sprague Dawley rats with varying degrees of myocardial stiffness induced by aortic constriction (n=38) and healthy controls (n=9) underwent echocardiography and CMR at approximately 13 weeks post-operation. Imaging biomarkers of diastolic function were evaluated for their ability to predict the EDPVR slope from pressure-volume recordings using regression analysis and receiver operating characteristics analysis. Results Both CMR and echocardiographic imaging biomarkers, in particular those related to the left atrium and mitral flow, were able to predict the EDPVR slope in a rat model with varying stiffness. From CMR, native T1 values, peak early diastolic longitudinal strain rate (SRe(long)) and E/SRe(long), left atrial (LA) ejection fraction, isovolumetric relaxation time (IVRT), E/A and peak LA strain, correlated best with the EDPVR slope (|r|=0.54–0.72). From echocardiography, E/A, E, LA diameter, e’/a’, E/SRe(long) and IVRT correlated with the EDPVR slope (|r|=0.49–0.67), while E/e’, e’ and E-wave deceleration time demonstrated poor correlation (|r|=0.17–0.27). Receiver operating characteristics analysis indicated better performance of CMR imaging biomarkers than echocardiography in predicting increased EDPVR slope. Conclusions Several diastolic imaging biomarkers commonly employed in preclinical studies have poor ability to predict cardiac chamber stiffness. Our study identifies several imaging biomarkers obtained from both echocardiography and CMR that are able to estimate LV chamber stiffness non-invasively, providing an important tool for future mechanistic research on myocardial stiffness.

• Ruud, Marianne; Frisk, Michael; Melleby, Arne Olav; Norseng, Per Andreas; Mohamed, Belal A. & Li, Jia [Show all 22 contributors for this article] (2024). Regulation of cardiomyocyte t-tubule structure by preload and afterload: Roles in cardiac compensation and decompensation. Journal of Physiology. ISSN 0022-3751. 602(18), p. 4487–4510. doi: 10.1113/JP284566. Full text in Research Archive Show summary

  Mechanical load is a potent regulator of cardiac structure and function. Although high workload during heart failure is associated with disruption of cardiomyocyte t-tubules and Ca2+ homeostasis, it remains unclear whether changes in preload and afterload may promote adaptive t-tubule remodelling. We examined this issue by first investigating isolated effects of stepwise increases in load in cultured rat papillary muscles. Both preload and afterload increases produced a biphasic response, with the highest t-tubule densities observed at moderate loads, whereas excessively low and high loads resulted in low t-tubule levels. To determine the baseline position of the heart on this bell-shaped curve, mice were subjected to mildly elevated preload or afterload (1 week of aortic shunt or banding). Both interventions resulted in compensated cardiac function linked to increased t-tubule density, consistent with ascension up the rising limb of the curve. Similar t-tubule proliferation was observed in human patients with moderately increased preload or afterload (mitral valve regurgitation, aortic stenosis). T-tubule growth was associated with larger Ca2+ transients, linked to upregulation of L-type Ca2+ channels, Na+–Ca2+ exchanger, mechanosensors and regulators of t-tubule structure. By contrast, marked elevation of cardiac load in rodents and patients advanced the heart down the declining limb of the t-tubule–load relationship. This bell-shaped relationship was lost in the absence of electrical stimulation, indicating a key role of systolic stress in controlling t-tubule plasticity. In conclusion, modest augmentation of workload promotes compensatory increases in t-tubule density and Ca2+ cycling, whereas this adaptation is reversed in overloaded hearts during heart failure progression.

• Vistnes, Maria; Erusappan, Pugazendhi Murugan; Sasi, Athiramol; Nordén, Einar Sjaastad; Bergo, Kaja Knudsen & Romaine, Andreas [Show all 22 contributors for this article] (2023). Inhibition of the extracellular enzyme A disintegrin and metalloprotease with thrombospondin motif 4 prevents cardiac fibrosis and dysfunction. Cardiovascular Research (CVR). ISSN 0008-6363. 119(10), p. 1915–1927. doi: 10.1093/cvr/cvad078. Full text in Research Archive Show summary

  Abstract Aims Heart failure is a condition with high mortality rates, and there is a lack of therapies that directly target maladaptive changes in the extracellular matrix (ECM), such as fibrosis. We investigated whether the ECM enzyme known as A disintegrin and metalloprotease with thrombospondin motif (ADAMTS) 4 might serve as a therapeutic target in treatment of heart failure and cardiac fibrosis. Methods and results The effects of pharmacological ADAMTS4 inhibition on cardiac function and fibrosis were examined in rats exposed to cardiac pressure overload. Disease mechanisms affected by the treatment were identified based on changes in the myocardial transcriptome. Following aortic banding, rats receiving an ADAMTS inhibitor, with high inhibitory capacity for ADAMTS4, showed substantially better cardiac function than vehicle-treated rats, including ∼30% reduction in E/e′ and left atrial diameter, indicating an improvement in diastolic function. ADAMTS inhibition also resulted in a marked reduction in myocardial collagen content and a down-regulation of transforming growth factor (TGF)-β target genes. The mechanism for the beneficial effects of ADAMTS inhibition was further studied in cultured human cardiac fibroblasts producing mature ECM. ADAMTS4 caused a 50% increase in the TGF-β levels in the medium. Simultaneously, ADAMTS4 elicited a not previously known cleavage of TGF-β-binding proteins, i.e. latent-binding protein of TGF-β and extra domain A-fibronectin. These effects were abolished by the ADAMTS inhibitor. In failing human hearts, we observed a marked increase in ADAMTS4 expression and cleavage activity. Conclusion Inhibition of ADAMTS4 improves cardiac function and reduces collagen accumulation in rats with cardiac pressure overload, possibly through a not previously known cleavage of molecules that control TGF-β availability. Targeting ADAMTS4 may serve as a novel strategy in heart failure treatment, in particular, in heart failure with fibrosis and diastolic dysfunction.

• Skogestad, Jonas; Albert, Ingrid; Hougen, Karina; Lothe, Gustav B; Lunde, Marianne & Eken, Olav Søvik [Show all 25 contributors for this article] (2023). Disruption of Phosphodiesterase 3A Binding to SERCA2 Increases SERCA2 Activity and Reduces Mortality in Mice with Chronic Heart Failure. Circulation. ISSN 0009-7322. 147(16), p. 1221–1236. doi: 10.1161/CIRCULATIONAHA.121.054168. Full text in Research Archive
• Sasi, Athiramol; Romaine, Andreas; Erusappan, Pugazendhi Murugan; Melleby, Arne Olav; Hasic, Almira & Dahl, Christen Peder [Show all 14 contributors for this article] (2023). Temporal expression and spatial distribution of the proteoglycan versican during cardiac fibrosis development. Matrix Biology Plus. 19-20. doi: 10.1016/j.mbplus.2023.100135. Full text in Research Archive Show summary

  Cardiac fibrosis is a central pathological feature in several cardiac diseases, but the underlying molecular players are insufficiently understood. The extracellular matrix proteoglycan versican is elevated in heart failure and suggested to be a target for treatment. However, the temporal expression and spatial distribution of versican and the versican cleavage fragment containing the neoepitope DPEAAE in cardiac fibrosis remains to be elucidated. In this study, we have examined versican during cardiac fibrosis development in a murine pressure overload model and in patients with cardiomyopathies. We found that versican, mainly the V1 isoform, was expressed immediately after induction of pressure overload, preceding collagen accumulation, and versican protein levels extended from the perivascular region into the cardiac interstitium. In addition, we found increased production of versican by collagen expressing fibroblasts, and that it was deposited extensively in the fibrotic extracellular matrix during pressure overload. In cardiac cell cultures, the expression of versican was induced by the pro-fibrotic transforming growth factor beta and mechanical stretch. Furthermore, we observed that the proteolytic cleavage of versican (DPEAAE fragment) increased in the late phase of fibrosis development during pressure overload. In patients with hypertrophic and dilated cardiomyopathies, we found elevated levels of versican and a positive correlation between versican and collagen mRNA in the heart, as well as increased cleavage of full-length protein. Taken together, the temporal expression profile and the spatial distribution of both the full-length versican and the DPEAAE fragment observed in this study indicates a role for versican in development of cardiac fibrosis.

• Tønnessen, Theis Christian; Melleby, Arne Olav; Hauge-Iversen, Ida Marie; Espe, Emil Knut Stenersen; Ahmed, Muhammad Shakil & Ueland, Thor [Show all 12 contributors for this article] (2022). Impact of delayed type hypersensitivity arthritis on development of heart failure by aortic constriction in mice. PLOS ONE. 17(1). doi: 10.1371/journal.pone.0262821. Full text in Research Archive Show summary

  Aims Patients with rheumatoid arthritis (RA) have increased risk of heart failure (HF). The mechanisms and cardiac prerequisites explaining this association remain unresolved. In this study, we sought to determine the potential cardiac impact of an experimental model of RA in mice subjected to HF by constriction of the ascending aorta. Methods Aorta was constricted via thoracotomy and placement of o-rings with inner diameter 0.55 mm or 0.66 mm, or sham operated. RA-like phenotype was instigated by delayed-type hypersensitivity arthritis (DTHA) two weeks after surgery and re-iterated after additional 18 days. Cardiac magnetic resonance imaging (MRI) was performed before surgery and at successive time points throughout the study. Six weeks after surgery the mice were euthanized, blood and tissue were collected, organ weights were documented, and expression levels of cardiac foetal genes were analysed. In a supplemental study, DTHA-mice were euthanized throughout 14 days after induction of arthritis, and blood was analysed for important markers and mediators of RA (SAP, TNF-α and IL-6). In order to put the latter findings into clinical context, the same molecules were analysed in serum from untreated RA patients and compared to healthy controls. Results Significant elevations of inflammatory markers were found in both patient- and murine blood. Furthermore, the DTHA model appeared clinically relevant when compared to the inflammatory responses observed in three prespecified RA severity disease states. Two distinct trajectories of cardiac dysfunction and HF development were found using the two o-ring sizes. These differences were consistent by both MRI, organ weights and cardiac foetal gene expression levels. Still, no difference within the HF groups, nor within the sham groups, could be found when DTHA was induced. Conclusion DTHA mediated systemic inflammation did not cause, nor modify HF caused by aortic constriction. This indicates other prerequisites for RA-induced cardiac dysfunction.

• Lunde, Ida Gjervold; Aronsen, Jan Magnus; Melleby, Arne Olav; Strand, Mari Elen; Skogestad, Jonas & Bendiksen, Bård Andre [Show all 11 contributors for this article] (2022). Cardiomyocyte-specific overexpression of syndecan-4 in mice results in activation of calcineurin-NFAT signalling and exacerbated cardiac hypertrophy. Molecular Biology Reports. ISSN 0301-4851. 49(12), p. 11795–11809. doi: 10.1007/s11033-022-07985-y. Full text in Research Archive Show summary

  Abstract Background Cardiomyocyte hypertrophy is a hallmark of cardiac dysfunction in patients with aortic stenosis (AS), and can be triggered by left ventricular (LV) pressure overload in mice by aortic banding (AB). Syndecan-4 is a transmembrane heparan sulphate proteoglycan which is found increased in the myocardium of AS patients and AB mice. The role of syndecan-4 in cardiomyocyte hypertrophy is not well understood. Purpose of the study We developed mice with cardiomyocyte-specific overexpression of syndecan-4 ( Sdc4-Tg ) and subjected these to AB to examine the role of syndecan-4 in hypertrophy and activation of the pro-hypertrophic calcineurin-NFAT signalling pathway. Methods and results Sdc4-Tg mice showed exacerbated cardiac remodelling upon AB compared to wild type (WT). At 2–6 weeks post-AB, Sdc4-Tg and WT mice showed similar hypertrophic growth, while at 20 weeks post-AB, exacerbated hypertrophy and dysfunction were evident in Sdc4-Tg mice. After cross-breeding of Sdc4-Tg mice with NFAT-luciferase reporter mice, we found increased NFAT activation in Sdc4-Tg hearts after AB. Immunoprecipitation showed that calcineurin bound to syndecan-4 in Sdc4-Tg hearts. Isolated cardiomyocytes from Sdc4-Tg mice showed alterations in Ca 2+ fluxes, suggesting that syndecan-4 regulated Ca 2+ levels, and thereby, activating the syndecan-4-calcineurin complex resulting in NFAT activation and hypertrophic growth. Similarly, primary cardiomyocyte cultures from neonatal rats showed increased calcineurin-NFAT-dependent hypertrophic growth upon viral Sdc4 overexpression. Conclusion Our study of mice with cardiomyocyte-specific overexpression of Sdc4 have revealed that syndecan-4 is important for activation of the Ca 2+ -dependent calcineurin-NFAT signalling pathway, hypertrophic remodelling and dysfunction in cardiomyocytes in response to pressure overload.

• Romaine, Andreas; Melleby, Arne Olav; Alam, Jahedul; Lobert, Viola; Lu, Ning & Lockwood, Francesca Eve [Show all 13 contributors for this article] (2022). Integrin α11β1 and syndecan-4 dual receptor ablation attenuates cardiac hypertrophy in the pressure overloaded heart. American Journal of Physiology. Heart and Circulatory Physiology. ISSN 0363-6135. 322(6), p. H1057–H1071. doi: 10.1152/ajpheart.00635.2021. Full text in Research Archive
• Rypdal, Karoline Bjarnesdatter; Melleby, Arne Olav; Robinson, Emma Louise; Li, Jia; Palmero, Sheryl & E., Seifert Deborah [Show all 20 contributors for this article] (2022). ADAMTSL3 knock-out mice develop cardiac dysfunction and dilatation with increased TGFβ signalling after pressure overload. Communications Biology. 5(1). doi: 10.1038/s42003-022-04361-1. Full text in Research Archive Show summary

  Abstract Heart failure is a major cause of morbidity and mortality worldwide, and can result from pressure overload, where cardiac remodelling is characterized by cardiomyocyte hypertrophy and death, fibrosis, and inflammation. In failing hearts, transforming growth factor (TGF)β drives cardiac fibroblast (CFB) to myofibroblast differentiation causing excessive extracellular matrix production and cardiac remodelling. New strategies to target pathological TGFβ signalling in heart failure are needed. Here we show that the secreted glycoprotein ADAMTSL3 regulates TGFβ in the heart. We found that Adamtsl3 knock-out mice develop exacerbated cardiac dysfunction and dilatation with increased mortality, and hearts show increased TGFβ activity and CFB activation after pressure overload by aortic banding. Further, ADAMTSL3 overexpression in cultured CFBs inhibits TGFβ signalling, myofibroblast differentiation and collagen synthesis, suggesting a cardioprotective role for ADAMTSL3 by regulating TGFβ activity and CFB phenotype. These results warrant future investigation of the potential beneficial effects of ADAMTSL3 in heart failure.

• Manfra, Ornella; Calamera, Gaia; Froese, Alexander; Arunthavarajah, Dulasi; Surdo, Nicoletta C. & Meier, Silja [Show all 14 contributors for this article] (2022). CNP regulates cardiac contractility and increases cGMP near both SERCA and TnI: difference from BNP visualized by targeted cGMP biosensors. Cardiovascular Research (CVR). ISSN 0008-6363. 118(6), p. 1506–1519. doi: 10.1093/cvr/cvab167. Full text in Research Archive Show summary

  Abstract Aims Guanylyl cyclase-B (GC-B; natriuretic peptide receptor-B, NPR-B) stimulation by C-type natriuretic peptide (CNP) increases cGMP and causes a lusitropic and negative inotropic response in adult myocardium. These effects are not mimicked by NPR-A (GC-A) stimulation by brain natriuretic peptide (BNP), despite similar cGMP increase. More refined methods are needed to better understand the mechanisms of the differential cGMP signalling and compartmentation. The aim of this work was to measure cGMP near proteins involved in regulating contractility to understand compartmentation of cGMP signalling in adult cardiomyocytes. Methods and results We constructed several fluorescence resonance energy transfer (FRET)-based biosensors for cGMP subcellularly targeted to phospholamban (PLB) and troponin I (TnI). CNP stimulation of adult rat cardiomyocytes increased cGMP near PLB and TnI, whereas BNP stimulation increased cGMP near PLB, but not TnI. The phosphodiesterases PDE2 and PDE3 constrained cGMP in both compartments. Local receptor stimulation aided by scanning ion conductance microscopy (SICM) combined with FRET revealed that CNP stimulation both in the t-tubules and on the cell crest increases cGMP similarly near both TnI and PLB. In ventricular strips, CNP stimulation, but not BNP, induced a lusitropic response, enhanced by inhibition of either PDE2 or PDE3, and a negative inotropic response. In cardiomyocytes from heart failure rats, CNP increased cGMP near PLB and TnI more pronounced than in cells from sham-operated animals. Conclusion These targeted biosensors demonstrate that CNP, but not BNP, increases cGMP near TnI in addition to PLB, explaining how CNP, but not BNP, is able to induce lusitropic and negative inotropic responses.

• Rypdal, Karoline Bjarnesdatter; Erusappan, Pugazendhi Murugan; Melleby, Arne Olav; Seifert, Deborah E.; Palmero, Sheryl & Strand, Mari Elen [Show all 13 contributors for this article] (2021). The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts. Scientific Reports. 11(1), p. 1–15. doi: 10.1038/s41598-021-99032-2. Full text in Research Archive Show summary

  Abstract Fibrosis accompanies most heart diseases and is associated with adverse patient outcomes. Transforming growth factor (TGF)β drives extracellular matrix remodelling and fibrosis in the failing heart. Some members of the ADAMTSL (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motifs-like) family of secreted glycoproteins bind to matrix microfibrils, and although their function in the heart remains largely unknown, they are suggested to regulate TGFβ activity. The aims of this study were to determine ADAMTSL2 levels in failing hearts, and to elucidate the role of ADAMTSL2 in fibrosis using cultured human cardiac fibroblasts (CFBs). Cardiac ADAMTSL2 mRNA was robustly increased in human and experimental heart failure, and mainly expressed by fibroblasts. Over-expression and treatment with extracellular ADAMTSL2 in human CFBs led to reduced TGFβ production and signalling. Increased ADAMTSL2 attenuated myofibroblast differentiation, with reduced expression of the signature molecules α-smooth muscle actin and osteopontin. Finally, ADAMTSL2 mitigated the pro-fibrotic CFB phenotypes, proliferation, migration and contractility. In conclusion, the extracellular matrix-localized glycoprotein ADAMTSL2 was upregulated in fibrotic and failing hearts of patients and mice. We identified ADAMTSL2 as a negative regulator of TGFβ in human cardiac fibroblasts, inhibiting myofibroblast differentiation and pro-fibrotic properties.

• Herum, Kate Louise Møller; Romaine, Andreas; Wang, Ariel; Melleby, Arne Olav; Strand, Mari Elen & Pacheco, Julian [Show all 16 contributors for this article] (2020). Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin. Journal of the American Heart Association (JAHA). 9(3). doi: 10.1161/JAHA.119.013518. Full text in Research Archive Show summary

  Background Pressure overload of the heart occurs in patients with hypertension or valvular stenosis and induces cardiac fibrosis because of excessive production of extracellular matrix by activated cardiac fibroblasts. This initially provides essential mechanical support to the heart, but eventually compromises function. Osteopontin is associated with fibrosis; however, the underlying signaling mechanisms are not well understood. Herein, we examine the effect of thrombin‐cleaved osteopontin on fibrosis in the heart and explore the role of syndecan‐4 in regulating cleavage of osteopontin. Methods and Results Osteopontin was upregulated and cleaved by thrombin in the pressure‐overloaded heart of mice subjected to aortic banding. Cleaved osteopontin was higher in plasma from patients with aortic stenosis receiving crystalloid compared with blood cardioplegia, likely because of less heparin‐induced inhibition of thrombin. Cleaved osteopontin and the specific osteopontin peptide sequence RGDSLAYGLR that is exposed after thrombin cleavage both induced collagen production in cardiac fibroblasts. Like osteopontin, the heparan sulfate proteoglycan syndecan‐4 was upregulated after aortic banding. Consistent with a heparan sulfate binding domain in the osteopontin cleavage site, syndecan‐4 was found to bind to osteopontin in left ventricles and cardiac fibroblasts and protected osteopontin from cleavage by thrombin. Shedding of the extracellular part of syndecan‐4 was more prominent at later remodeling phases, at which time levels of cleaved osteopontin were increased. Conclusions Thrombin‐cleaved osteopontin induces collagen production by cardiac fibroblasts. Syndecan‐4 protects osteopontin from cleavage by thrombin, but this protection is lost when syndecan‐4 is shed in later phases of remodeling, contributing to progression of cardiac fibrosis.

• Melleby, Arne Olav; Sandvik, Guro Katrine; Couturier, Christine Stephanie; Nilsson, Göran Erik & Stecyk, Jonathan Anthony William (2020). H2S-producing enzymes in anoxia-tolerant vertebrates: Effects of cold acclimation, anoxia exposure and reoxygenation on gene and protein expression. Comparative Biochemistry and Physiology - Part B: Biochemistry & Molecular Biology. ISSN 1096-4959. 243-244. doi: 10.1016/j.cbpb.2020.110430. Full text in Research Archive
• Mohammadzadeh, Naiyereh; Melleby, Arne Olav; Palmero, Sheryl; Sjaastad, Ivar; Chakravarti, Shukti & Engebretsen, Kristin V Thunheim [Show all 9 contributors for this article] (2020). Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload. Cardiology. ISSN 0008-6312. 145(3), p. 187–198. doi: 10.1159/000505318. Full text in Research Archive
• Alam, Jahedul; Musiime, Moses; Romaine, Andreas; Sawant, Mugdha; Melleby, Arne Olav & Lu, Ning [Show all 9 contributors for this article] (2020). Generation of a novel mouse strain with fibroblast-specific expression of Cre recombinase. Matrix Biology Plus. 8. doi: 10.1016/j.mbplus.2020.100045. Full text in Research Archive Show summary

  Cell-specific expression of genes offers the possibility to use their promoters to drive expression of Cre-recombinase, thereby allowing for detailed expression analysis using reporter gene systems, cell lineage tracing, conditional gene deletion, and cell ablation. In this context, current data suggest that the integrin α11 subunit has the potential to serve as a fibroblast biomarker in tissue regeneration and pathology, in particular in wound healing and in tissue- and tumor fibrosis. The mesenchyme-restricted expression pattern of integrin α11 thus prompted us to generate a novel ITGA11-driver Cre mouse strain using a ϕC31 integrase-mediated knock-in approach. In this transgenic mouse, the Cre recombinase is driven by regulatory promoter elements within the 3 kb segment of the human ITGA11 gene. β-Galactosidase staining of embryonic tissues obtained from a transgenic ITGA11-Cre mouse line crossed with Rosa 26R reporter mice (ITGA11-Cre;R26R) revealed ITGA11-driven Cre expression and activity in mesenchymal cells in a variety of mesenchymal tissues in a pattern reminiscent of endogenous α11 protein expression in mouse embryos. Interestingly, X-gal staining of mouse embryonic fibroblasts (MEFs) isolated from the ITGA11-Cre;R26R mice indicated heterogeneity in the MEF population. ITGA11-driven Cre activity was shown in approximately 60% of the MEFs, suggesting that the expression of integrin α11 could be exploited for isolation of different fibroblast populations. ITGA11-driven Cre expression was found to be low in adult mouse tissues but was induced in granulation tissue of excisional wounds and in fibrotic hearts following aortic banding. We predict that the ITGA11-Cre transgenic mouse strain described in this report will be a useful tool in matrix research for the deletion of genes in subsets of fibroblasts in the developing mouse and for determining the function of subsets of pro-fibrotic fibroblasts in tissue fibrosis and in different subsets of cancer-associated fibroblasts in the tumor microenvironment.

• Melleby, Arne Olav; Romaine, Andreas; Aronsen, Jan Magnus; Veras, Ioanni; Zhang, Lili & Sjaastad, Ivar [Show all 8 contributors for this article] (2018). A novel method for high precision aortic constriction that allows for generation of specific cardiac phenotypes in mice. Cardiovascular Research (CVR). ISSN 0008-6363. doi: 10.1093/cvr/cvy141. Full text in Research Archive Show summary

  Aims Generation of reproducible cardiac disease phenotypes in mice is instrumental for investigating mechanisms leading to heart failure (HF). For decades, suture-based thoracic aortic constriction has been the preferred method for increasing left ventricular (LV) afterload in rodents, but the degree of stenosis resulting from this method is variable. In an effort to improve this methodology, we subjected mice to constriction of the ascending aorta using o-rings with fixed inner diameters (IDs). Methods and results Mice of C57BL/6J and FVB/N background were subjected to constriction of the ascending aorta using o-rings with fixed IDs of 0.71, 0.66, and 0.61 mm. O-ring aortic banding resulted in 98.7% survival 2 weeks post-surgery, with very low intra- and inter-surgeon variation. When using the narrowest o-ring (0.61 mm), mice developed hypertrophy within 1 week. Over 20 weeks, the mice gradually developed reduced LV ejection fraction (LVEF) and dilatation with increased left atrial dimensions and lung weight, indicating congestion. When using o-rings with IDs of 0.66 mm and 0.71 mm, the mice developed hypertrophy, but maintained a compensated state with stabilized LVEF 8–20 weeks post-surgery. The up-regulation of signature genes associated with HF, hypertrophy, fibrosis, and the level of activation of MAPK and NFAT signalling pathways corresponded to the degree of stenosis. Conclusion Here, we introduce a novel method for high precision aortic constriction in mice with high intra- and inter-surgeon reproducibility and low post-operative mortality that allows generation of specific cardiac disease phenotypes.

• Romaine, Andreas; Sørensen, Ida Wiig; Zeltz, Cedric; Lu, Ning; Erusappan, Pugazendhi Murugan & Melleby, Arne Olav [Show all 15 contributors for this article] (2017). Overexpression of integrin α11 induces cardiac fibrosis in mice. Acta Physiologica Scandinavica. ISSN 0001-6772. 222:e13025(2), p. 1–17. doi: 10.1111/apha.12932. Full text in Research Archive
• Melleby, Arne Olav; Strand, Mari Elen; Romaine, Andreas; Herum, Kate Louise Møller; Skrbic, Biljana & Dahl, Christen Peder [Show all 11 contributors for this article] (2016). The heparan sulfate proteoglycan glypican-6 is upregulated in the failing heart, and regulates cardiomyocyte growth through ERK1/2 Signaling. PLOS ONE. 11(10). doi: 10.1371/journal.pone.0165079. Full text in Research Archive

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• Aronsen, Jan Magnus; Skogestad, Jonas; Albert, Ingrid; Melleby, Arne Olav & Carlson, Cathrine Rein (2023). Response by Aronsen et al to Letter Regarding Article, "Disruption of Phosphodiesterase 3A Binding to SERCA2 Increases SERCA2 Activity and Reduces Mortality in Mice With Chronic Heart Failure". Circulation. ISSN 0009-7322. 148(10), p. 857–858. doi: 10.1161/CIRCULATIONAHA.123.065884. Full text in Research Archive
• Melleby, Arne Olav; Strand, Mari Elen; Herum, Kate Louise Møller; Skrbic, Biljana; Dahl, Christen Peder & Sjaastad, Ivar [Show all 10 contributors for this article] (2016). Glypican-6 is upregulated in heart failure and mediates cardiomyocyte growth through ERK1/2 signaling. Full text in Research Archive
• Romaine, Andreas; Sørensen, Ida Wiig; Melleby, Arne Olav; Zeltz, Cedric; Zhang, Lili & Bendiksen, Bård Andre [Show all 12 contributors for this article] (2016). Overexpression of integrin a11 induces cardiac hypertrophy and fibrosis. Full text in Research Archive
• Melleby, Arne Olav; Strand, Mari Elen; Herum, Kate Louise Møller; Skrbic, Biljana; Dahl, Christen Peder & Sjaastad, Ivar [Show all 10 contributors for this article] (2015). Glypican-6 is increased in experimental and clinical heart failure and might play a role in cardiac fibrosis through BMP4 signalling. Full text in Research Archive
• Melleby, Arne Olav; Strand, Mari Elen; Skrbic, Biljana; Dahl, Christen Peder; Tønnessen, Theis & Sjaastad, Ivar [Show all 10 contributors for this article] (2014). Glypican 6 is up-regulated in pressure overload induced pathological left ventricular remodeling, mediates bFGF signaling and may affect cardiac fibrosis development. Full text in Research Archive
• Melleby, Arne Olav; Strand, Mari Elen; Skrbic, Biljana; Dahl, Christen Peder; Tønnessen, Theis & Sjaastad, Ivar [Show all 10 contributors for this article] (2014). The heparan sulfate proteoglycan glypican-6 is increased in experimental and clinical heart failure and might play a role in myocardial fibrosis. European Journal of Heart Failure. ISSN 1388-9842. 16, p. 116–116. Full text in Research Archive

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