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• Strand, Mari Elen; Vanhaverbeke, Maarten; Henkens, Michiel T. H. M.; Sikking, Maurits A.; Rypdal, Karoline Bjarnesdatter & Braathen, Bjørn [Show all 11 contributors for this article] (2023). Inflammation and Syndecan-4 Shedding from Cardiac Cells in Ischemic and Non-Ischemic Heart Disease. Biomedicines. 11(4). doi: 10.3390/biomedicines11041066. Full text in Research Archive Show summary

  Circulating biomarkers reflecting cardiac inflammation are needed to improve the diagnostics and guide the treatment of heart failure patients. The cardiac production and shedding of the transmembrane proteoglycan syndecan-4 is upregulated by innate immunity signaling pathways. Here, we investigated the potential of syndecan-4 as a blood biomarker of cardiac inflammation. Serum syndecan-4 was measured in patients with (i) non-ischemic, non-valvular dilated cardiomyopathy (DCM), with (n = 71) or without (n = 318) chronic inflammation; (ii) acute myocarditis (n = 15), acute pericarditis (n = 3) or acute perimyocarditis (23) and (iii) acute myocardial infarction (MI) at day 0, 3 and 30 (n = 119). Syndecan-4 was investigated in cultured cardiac myocytes and fibroblasts (n = 6–12) treated with the pro-inflammatory cytokines interleukin (IL)-1β and its inhibitor IL-1 receptor antagonist (IL-1Ra), or tumor necrosis factor (TNF)α and its specific inhibitor infliximab, an antibody used in treatment of autoimmune diseases. The levels of serum syndecan-4 were comparable in all subgroups of patients with chronic or acute cardiomyopathy, independent of inflammation. Post-MI, syndecan-4 levels were increased at day 3 and 30 vs. day 0. IL-1Ra attenuated IL-1β-induced syndecan-4 production and shedding in vitro, while infliximab had no effect. In conclusion, syndecan-4 shedding from cardiac myocytes and fibroblasts was attenuated by immunomodulatory therapy. Although its circulating levels were increased post-MI, syndecan-4 did not reflect cardiac inflammatory status in patients with heart disease.

• 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.

• Andenæs, Kine; Rypdal, Karoline Bjarnesdatter; Palmero, Sheryl; Tønnessen, Theis & Lunde, Ida Gjervold (2022). The small leucine-rich proteoglycan fibromodulin exerts anti-fibrotic effects in cultured human cardiac fibroblasts. Genetics and Molecular Research. 21(1). doi: 10.4238/gmr19007. Full text in Research Archive Show summary

  Cardiac fibrosis is common and detrimental in numerous heart diseases, affecting millions of patients worldwide. Cardiac fibrosis is characterized by excessive production of extracellular matrix (ECM) constituents such as fibrillar collagens, produced by activated cardiac fibroblasts, i.e.: myofibroblasts. Therapeutic targeting of cardiac fibrosis is highly attractive; however, it remains a major medical challenge. Fibromodulin is a small leucine-rich proteoglycan localized in the ECM. Fibromodulin binds to collagen fibrils, and plays a critical role in collagen fibrillogenesis, ECM organization, wound healing and regulation of the pro-fibrotic cytokine transforming growth factor beta (TGFβ) in several organs. Fibromodulin is highly upregulated in mice and patients with heart failure, but little is known about its role in cardiac fibrosis. Our recent findings from primary cultures of cardiac fibroblasts from neonatal rat hearts suggest that fibromodulin has anti-fibrotic effects. Here we investigated the translational value of these findings by overexpressing fibromodulin in cultured human fetal and adult cardiac fibroblasts. The effects of fibromodulin overexpression on gene expression were measured by qPCR and gene arrays, whereas protein levels were measured by Western blotting, and collagen synthesis by radioactive proline incorporation. The results support our previous findings and indicate relevance for human disease. We found that fibromodulin reduced the expression levels of the collagen cross-linking enzymes lysyl oxidase (LOX) and transglutaminase 2 (TGM2). Fibromodulin also reduced the levels of connective tissue growth factor (CTGF) and periostin (POSTN), indicating reduced TGFβ activity. Reduced levels of intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) suggested reduced potential for immune cell adhesion, and gene arrays indicated altered integrin expression, suggesting altered ECM-cell adhesion. Expression of fibrillar collagens was unaffected. In conclusion, fibromodulin reduced TGFβ activity and down-regulated central collagen-crosslinking enzymes, in line with an anti-fibrotic effect of fibromodulin in human cardiac fibroblasts.

• 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.

• Pope, Marita Knudsen; Ratajska, Aleksandra; Johnsen, Hilde; Rypdal, Karoline Bjarnesdatter; Sejersted, Yngve & Paus, Benedicte (2019). Diagnostics of Hereditary Connective Tissue Disorders by Genetic Next-Generation Sequencing. Genetic Testing and Molecular Biomarkers. ISSN 1945-0265. 23(11), p. 783–790. doi: 10.1089/gtmb.2019.0064. Full text in Research Archive Show summary

  Aims: This quality analysis study was designed to review the indications, reports, and clinical consequences of 438 diagnostic next-generation sequencing (NGS) gene panel analyses for hereditary connective tissue disorders (HCTD). Methods: Molecular analyses were retrieved from laboratory databases and patient records, and compared to the clinical information in the requisition and classified according to the Human Phenotype Ontology. Results: In 123 of 438 NGS analyses, 156 sequence variants were reported in 33 of 54 genes analyzed. NGS analyses and, in some cases, postanalytic assessment resulted in identification of pathogenic variants in 40 (9%) of patients, and variants of uncertain significance were identified in 83 (19%) of cases analyzed. While cardiovascular abnormalities were the most common phenotype noted in the requisitions, no specific organ system could be identified in which the reported symptoms provided an actionable indication for the analysis. Certain health issues recorded in the patients’ records were found to be frequently left out of requisitions. Conclusions: The interpretation of genetic sequence variants continues to be a significant challenge in HCTD. Although not associated with the highest diagnostic yield, cardiovascular disease and family history may be suitable indications for NGS due to the clinical consequences of the identification of a known or likely causative sequence variant for a vascular HCTD in patients and relatives.

• Sitek, Jan Cezary; Kulseth, Mari Ann; Rypdal, Karoline Bjarnesdatter; Skodje, Tove; Sheng, Ying & Retterstøl, Lars (2018). Whole-exome sequencing for diagnosis of hereditary ichthyosis. Journal of the European Academy of Dermatology and Venereology. ISSN 0926-9959. 32(6), p. 1022–1027. doi: 10.1111/jdv.14870. Full text in Research Archive
• Zook, Justin M.; Catoe, David; Rypdal, Karoline Bjarnesdatter; Sheng, Ying & Salit, Marc (2016). Extensive sequencing of seven human genomes to characterize benchmark reference materials. Scientific Data. doi: 10.1038/sdata.2016.25. Full text in Research Archive

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• Rypdal, Karoline Bjarnesdatter; Apte, Suneel S. & Lunde, Ida Gjervold (2024). Emerging roles for the ADAMTS-like family of matricellular proteins in cardiovascular disease through regulation of the extracellular microenvironment. Molecular Biology Reports. ISSN 0301-4851. doi: 10.1007/s11033-024-09255-5. Full text in Research Archive
• Lunde, Ida Gjervold; Rypdal, Karoline Bjarnesdatter; Linthout, Sophie Van; Diez, Javier & González, Arantxa (2024). Myocardial fibrosis from the perspective of the extracellular matrix: Mechanisms to clinical impact. Matrix Biology. ISSN 0945-053X. 134, p. 1–22. doi: 10.1016/j.matbio.2024.08.008. Full text in Research Archive

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