المؤلفون: Boel, Esper, Huge-Jensen, Birgitte, Wöldike, Helle F., Gormsen, Erik, Christensen, Mogens, Andreasen, Frank, Thim, Lars

المساهمون: Novo Nordisk A/S, Novo Allé, DK-2880 Bagsveerd, Denmark

الوصف: Triglyceride lipases from various organisms have a numberof potential industrial applications exemplified by their use in flavour enhancement, in production of esters and specialty fats, and in household detergents. We have cloned and expressed two fungallipases: the 1,3-positional specific lipase from Rhizomucor miehei (1,2), commercialized as Lipozyme™, and lipase from Humicola lanuginosa commercialized for use in household detergents (Lipolase™). Production of these lipases and other enzymesforindustrial application has necessitated the developmentof an efficient recombinant expression system. We have focusedour efforts on the development of Aspergillus as a recombinant host system for this purpose. Aspergillus has the capacity to secrete large amounts of active hydrolytic enzymes such as for example glucoamylases and amylases. Cloning of strong promoters from the corresponding genes (3,4) and development of a transformation- and selection system (4) has allowed expression from heterologous cDNA genesin Aspergillus oryzae. As first attempt to obtain heterologous expression we transferred an aspartic proteinase cDNA (5) from Rhizomucor miehei into A. oryzae and obtained high levels of secreted, active and correctly processed enzyme (4). These experiments have later been extended to fungal triglyceride lipases (6,7).

العلاقة: GBF monographs; Volume 16; Lipases : structure, mechanism and genetic engineering, 207 - 219; 156081165X; http://hdl.handle.net/10033/623718Test; Lipases : structure, mechanism and genetic engineering, 1991

الإتاحة: http://hdl.handle.net/10033/623718Test

المؤلفون: Johnson, Robert T, Solanki, Reesha, Wostear, Finn, Ahmed, Sultan, Taylor, James CK, Rees, Jasmine, Abel, Geraad, McColl, James, Jørgensen, Helle F, Morris, Chris J, Bidula, Stefan, Warren, Derek T

مصطلحات موضوعية: aquaporin‐1, cell volume, matrix rigidity, piezo1, vascular smooth muscle, Extracellular Matrix, Humans, Myocytes, Smooth Muscle, Muscle, Smooth, Vascular, Ion Channels, Cell Size, Cells, Cultured, Animals, Hydrogels, Aorta

الوصف: Publication status: Published ; BACKGROUND AND PURPOSE: Decreased aortic compliance is a precursor to numerous cardiovascular diseases. Compliance is regulated by the rigidity of the aortic wall and the vascular smooth muscle cells (VSMCs). Extracellular matrix stiffening, observed during ageing, reduces compliance. In response to increased rigidity, VSMCs generate enhanced contractile forces that result in VSMC stiffening and a further reduction in compliance. Mechanisms driving VSMC response to matrix rigidity remain poorly defined. EXPERIMENTAL APPROACH: Human aortic-VSMCs were seeded onto polyacrylamide hydrogels whose rigidity mimicked either healthy (12 kPa) or aged/diseased (72 kPa) aortae. VSMCs were treated with pharmacological agents prior to agonist stimulation to identify regulators of VSMC volume regulation. KEY RESULTS: On pliable matrices, VSMCs contracted and decreased in cell area. Meanwhile, on rigid matrices VSMCs displayed a hypertrophic-like response, increasing in area and volume. Piezo1 activation stimulated increased VSMC volume by promoting calcium ion influx and subsequent activation of PKC and aquaporin-1. Pharmacological blockade of this pathway prevented the enhanced VSMC volume response on rigid matrices whilst maintaining contractility on pliable matrices. Importantly, both piezo1 and aquaporin-1 gene expression were up-regulated during VSMC phenotypic modulation in atherosclerosis and after carotid ligation. CONCLUSIONS AND IMPLICATIONS: In response to extracellular matrix rigidity, VSMC volume is increased by a piezo1/PKC/aquaporin-1 mediated pathway. Pharmacological targeting of this pathway specifically blocks the matrix rigidity enhanced VSMC volume response, leaving VSMC contractility on healthy mimicking matrices intact. Importantly, upregulation of both piezo1 and aquaporin-1 gene expression is observed in disease relevant VSMC phenotypes.

وصف الملف: text/xml; application/pdf

العلاقة: https://www.repository.cam.ac.uk/handle/1810/363830Test

الإتاحة: https://www.repository.cam.ac.uk/handle/1810/363830Test

المؤلفون: Proestakis, Ermis, Christensen, Helle F., Meireles, Leonardo T.P., Storebø, Einar Madsen, Shamsolhodaei, Amirhossein, Orlander, Tobias

المصدر: Proestakis , E , Christensen , H F , Meireles , L T P , Storebø , E M , Shamsolhodaei , A & Orlander , T 2024 , ' Detection and picking of shear wave arrival for stiffness evaluation of highly porous chalk ' , Geophysical Prospecting , vol. 72 , pp. 733–751 . https://doi.org/10.1111/1365-2478.13435Test

مصطلحات موضوعية: Full waveform, Rock physics, Shear wave, Ultrasonic velocity, Velocity analysis

الوصف: Elastic wave velocities of compressional and shear waves propagating through sedimentary rocks are often coupled with information of bulk density to derive the rock stiffness. Acquiring the transit time of compressional and shear waves often involves manual picking of wave arrival times from wave trains recorded in the laboratory or by well-logging tools. Picking the compressional wave arrival time is commonly accepted as straightforward. Oppositely, detecting the shear wave arrival and picking its arrival time is often troublesome because the transmitted shear wave partly converts to compressional waves and back to a secondary shear wave, concealing the transmitted shear wave arrival in the wave train. In laboratory settings, we illustrate the difficulty of shear wave detection in wave trains recorded on highly porous chalk plug samples from the Danish North Sea Basin. Wave trains were recorded on plugs dry, Tap-water or Isopar-L saturated during uniaxial strain compaction. The recorded shear wave trains showed two distinct features, which could be interpreted as the transmitted shear wave first arrival; we denoted them as early and late arrivals. However, as only one feature can mark the arrival of the transmitted shear wave, we propose a semi-empirical disclosure strategy combining a graphical representation of stacked wave trains with rock physical modelling. By stacking recorded wave trains in a graphical strain–time–amplitude domain, we demonstrate that an early shear wave feature marks a converted shear to compressional to shear wave and not the transmitted shear wave. We used physical modelling to identify early shear wave features and illustrate the consequences of adopting a falsely interpreted shear wave on stiffness properties.

وصف الملف: application/pdf

العلاقة: https://orbit.dtu.dk/en/publications/d4c27881-9056-4cd1-a6e3-b22c6f191a19Test

الإتاحة: https://doi.org/10.1111/1365-2478.13435Test
https://orbit.dtu.dk/en/publications/d4c27881-9056-4cd1-a6e3-b22c6f191a19Test
https://backend.orbit.dtu.dk/ws/files/355067043/Geophysical_Prospecting_-_2023_-_Proestakis_-_Detection_and_picking_of_shear_wave_arrival_for_stiffness_evaluation_of.pdfTest

المؤلفون: Johnson, Robert T., Solanki, Reesha, Wostear, Finn, Ahmed, Sultan, Taylor, James C. K., Rees, Jasmine, Abel, Geraad, McColl, James, Jørgensen, Helle F., Morris, Chris J., Bidula, Stefan, Warren, Derek T.

المساهمون: British Heart Foundation, Biotechnology and Biological Sciences Research Council

المصدر: British Journal of Pharmacology ; volume 181, issue 11, page 1576-1595 ; ISSN 0007-1188 1476-5381

الوصف: Background and Purpose Decreased aortic compliance is a precursor to numerous cardiovascular diseases. Compliance is regulated by the rigidity of the aortic wall and the vascular smooth muscle cells (VSMCs). Extracellular matrix stiffening, observed during ageing, reduces compliance. In response to increased rigidity, VSMCs generate enhanced contractile forces that result in VSMC stiffening and a further reduction in compliance. Mechanisms driving VSMC response to matrix rigidity remain poorly defined. Experimental Approach Human aortic‐VSMCs were seeded onto polyacrylamide hydrogels whose rigidity mimicked either healthy (12 kPa) or aged/diseased (72 kPa) aortae. VSMCs were treated with pharmacological agents prior to agonist stimulation to identify regulators of VSMC volume regulation. Key Results On pliable matrices, VSMCs contracted and decreased in cell area. Meanwhile, on rigid matrices VSMCs displayed a hypertrophic‐like response, increasing in area and volume. Piezo1 activation stimulated increased VSMC volume by promoting calcium ion influx and subsequent activation of PKC and aquaporin‐1. Pharmacological blockade of this pathway prevented the enhanced VSMC volume response on rigid matrices whilst maintaining contractility on pliable matrices. Importantly, both piezo1 and aquaporin‐1 gene expression were up‐regulated during VSMC phenotypic modulation in atherosclerosis and after carotid ligation. Conclusions and Implications In response to extracellular matrix rigidity, VSMC volume is increased by a piezo1/PKC/aquaporin‐1 mediated pathway. Pharmacological targeting of this pathway specifically blocks the matrix rigidity enhanced VSMC volume response, leaving VSMC contractility on healthy mimicking matrices intact. Importantly, upregulation of both piezo1 and aquaporin‐1 gene expression is observed in disease relevant VSMC phenotypes.

الإتاحة: https://doi.org/10.1111/bph.16294Test

المؤلفون: Lambert, Jordi, Oc, Sebnem, Worssam, Matthew D, Häußler, Daniel, Solomon, Charles U, Figg, Nichola L, Baxter, Ruby, Imaz, Maria, Taylor, James CK, Foote, Kirsty, Finigan, Alison, Mahbubani, Krishnaa T, Webb, Tom R, Ye, Shu, Bennett, Martin R, Krüger, Achim, Spivakov, Mikhail, Jørgensen, Helle F

مصطلحات موضوعية: Epigenomics, Regulatory networks, Transcriptomics, Vascular diseases

الوصف: Funder: Deutsche Forschungsgemeinschaft, Bonn, Germany: KR2047/8-1, KR2047/14-1, and KR2047/15-1 ; Funder: Chan Zuckerberg Initiative 2018-190766/RG98793 ; Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize vascular diseases causing heart attack and stroke. Here we elucidate molecular determinants governing VSMC proliferation by reconstructing gene regulatory networks from single-cell transcriptomics and epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. We compared gene regulatory network rewiring between injury-responsive and nonresponsive VSMCs, which suggested shared transcription factors but differing target loci between VSMC states. Through in silico perturbation analysis, we identified and prioritized previously unrecognized regulators of proliferation, including RUNX1 and TIMP1. Moreover, we showed that the pioneer transcription factor RUNX1 increased VSMC responsiveness and that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signaling. Both RUNX1 and the TIMP1-CD74 axis were expressed in human VSMCs, showing low levels in normal arteries and increased expression in disease, suggesting clinical relevance and potential as vascular disease targets. ; This work was supported by the British Heart Foundation (PG/19/6/34153, FS/15/62/32032, FS/15/38/31516, RM/13/3/30159, RE/13/ 6/30180, RE/18/1/34212, CH/2000003/12800, PG/23/11350, M.R.B., H.F.J., M. S.; RG/16/13/32609, RG/19/9/34655, PG/16/9/31995, PG/18/73/34059, SP/19/2/344612, S.Y., T.R.W.; AA/18/3/34220, C.U.S.), the Cambridge NIHR Biomedical Research Centre, the Deutsche Forschungsgemeinschaft, Bonn, Germany (KR2047/8-2, KR2047/14-1, KR2047/15-1, KR2047/16-1, A.K.), the Medical Research Council of the UK (MC-A652-5QA20, M.S., core-funded investigator), Singapore's National Medical Research Council (CIRG22jul‐0002, S.Y.), National University of Singapore and National University Health System ...

وصف الملف: application/pdf; application/zip; text/xml

العلاقة: https://www.repository.cam.ac.uk/handle/1810/369876Test

الإتاحة: https://www.repository.cam.ac.uk/handle/1810/369876Test

المؤلفون: Ćorović, Andrej, Wall, Christopher, Nus, Meritxell, Gopalan, Deepa, Huang, Yuan, Imaz, Maria, Zulcinski, Michal, Peverelli, Marta, Uryga, Anna, Lambert, Jordi, Bressan, Dario, Maughan, Robert T, Pericleous, Charis, Dubash, Suraiya, Jordan, Natasha, Jayne, David R, Hoole, Stephen P, Calvert, Patrick A, Dean, Andrew F, Doris Rassl, Barwick, Tara, Iles, Mark, Frontini, Mattia, Hannon, Greg, Manavaki, Roido, Fryer, Tim D, Aloj, Luigi, Graves, Martin J, Gilbert, Fiona J, Dweck, Marc R, Newby, David E, Fayad, Zahi A, Reynolds, Gary, Morgan, Ann W, Aboagye, Eric O, Davenport, Anthony P, Jørgensen, Helle F, Mallat, Ziad, Bennett, Martin R, Peters, James E, Rudd, James H F, Mason, Justin C, Tarkin, Jason M

مصطلحات موضوعية: Takayasu arteritis, atherosclerosis, giant cell arteritis, inflammation, molecular imaging, somatostatin receptor

الوصف: Background: Assessing inflammatory disease activity in large vessel vasculitis (LVV) can be challenging by conventional measures. Objectives: We aimed to investigate somatostatin receptor 2 (SST2) as a novel inflammation-specific molecular imaging target in LVV. Methods: In a prospective, observational cohort study, in vivo arterial SST2 expression was assessed by positron emission tomography/magnetic resonance imaging (PET/MRI) using 68Ga-DOTATATE and 18F-FET-βAG-TOCA. Ex vivo mapping of the imaging target was performed using immunofluorescence microscopy; imaging mass cytometry; and bulk, single-cell, and single-nucleus RNA sequencing. Results: Sixty-one participants (LVV: n = 27; recent atherosclerotic myocardial infarction of ≤2 weeks: n = 25; control subjects with an oncologic indication for imaging: n = 9) were included. Index vessel SST2 maximum tissue-to-blood ratio was 61.8% (P < 0.0001) higher in active/grumbling LVV than inactive LVV and 34.6% (P = 0.0002) higher than myocardial infarction, with good diagnostic accuracy (area under the curve: ≥0.86; P < 0.001 for both). Arterial SST2 signal was not elevated in any of the control subjects. SST2 PET/MRI was generally consistent with 18F-fluorodeoxyglucose PET/computed tomography imaging in LVV patients with contemporaneous clinical scans but with very low background signal in the brain and heart, allowing for unimpeded assessment of nearby coronary, myocardial, and intracranial artery involvement. Clinically effective treatment for LVV was associated with a 0.49 ± 0.24 (standard error of the mean [SEM]) (P = 0.04; 22.3%) reduction in the SST2 maximum tissue-to-blood ratio after 9.3 ± 3.2 months. SST2 expression was localized to macrophages, pericytes, and perivascular adipocytes in vasculitis specimens, with specific receptor binding confirmed by autoradiography. SSTR2-expressing macrophages coexpressed proinflammatory markers. Conclusions: SST2 PET/MRI holds major promise for diagnosis and therapeutic monitoring in LVV. (PET Imaging of Giant Cell ...

العلاقة: info:eu-repo/grantAgreement/EC/H2020/813545/; https://zenodo.org/communities/itn_helicalTest; https://zenodo.org/record/7912981Test; https://doi.org/10.1016/j.jacc.2022.10.034Test; oai:zenodo.org:7912981

الإتاحة: https://doi.org/10.1016/j.jacc.2022.10.034Test
https://zenodo.org/record/7912981Test

المؤلفون: de Winther, Menno P J, Bäck, Magnus, Evans, Paul C, Gomez, Delphine, Goncalves, Isabel, Jørgensen, Helle F, Koenen, Rory R, Lutgens, Esther, Norata, Giuseppe Danilo, Osto, Elena, Dib, Lea, Simons, Michael, Stellos, Konstantinos, Ylä-Herttuala, Seppo, Winkels, Holger, Bochaton-Piallat, Marie-Luce, Monaco, Claudia

المصدر: de Winther, Menno P J; Bäck, Magnus; Evans, Paul C; Gomez, Delphine; Goncalves, Isabel; Jørgensen, Helle F; Koenen, Rory R; Lutgens, Esther; Norata, Giuseppe Danilo; Osto, Elena; Dib, Lea; Simons, Michael; Stellos, Konstantinos; Ylä-Herttuala, Seppo; Winkels, Holger; Bochaton-Piallat, Marie-Luce; Monaco, Claudia (2023). Translational opportunities of single-cell biology in atherosclerosis. European Heart Journal, 44(14):1216-1230.

مصطلحات موضوعية: Institute of Clinical Chemistry, Clinic for Cardiology, 610 Medicine & health, 540 Chemistry

الوصف: The advent of single-cell biology opens a new chapter for understanding human biological processes and for diagnosing, monitoring, and treating disease. This revolution now reaches the field of cardiovascular disease (CVD). New technologies to interrogate CVD samples at single-cell resolution are allowing the identification of novel cell communities that are important in shaping disease development and direct towards new therapeutic strategies. These approaches have begun to revolutionize atherosclerosis pathology and redraw our understanding of disease development. This review discusses the state-of-the-art of single-cell analysis of atherosclerotic plaques, with a particular focus on human lesions, and presents the current resolution of cellular subpopulations and their heterogeneity and plasticity in relation to clinically relevant features. Opportunities and pitfalls of current technologies as well as the clinical impact of single-cell technologies in CVD patient care are highlighted, advocating for multidisciplinary and international collaborative efforts to join the cellular dots of CVD.

وصف الملف: application/pdf

العلاقة: https://www.zora.uzh.ch/id/eprint/226367/1/ZORA_226367.pdfTest; info:pmid/36478058; urn:issn:0195-668X

الإتاحة: https://doi.org/10.5167/uzh-22636710.1093/eurheartj/ehac686Test
https://www.zora.uzh.ch/id/eprint/226367Test/
https://www.zora.uzh.ch/id/eprint/226367/1/ZORA_226367.pdfTest

المؤلفون: Schoenmakers, Erik, Marelli, Federica, Jørgensen, Helle F., Visser, W. Edward, Moran, Carla, Groeneweg, Stefan, Avalos, Carolina, Jurgens, Sean J., Figg, Nichola, Finigan, Alison, Wali, Neha, Agostini, Maura, Wardle-Jones, Hannah, Lyons, Greta, Rusk, Rosemary, Gopalan, Deepa, Twiss, Philip, Visser, Jacob J., Goddard, Martin, Nashef, Samer A.M., Heijmen, Robin, Clift, Paul, Sinha, Sanjay, Pirruccello, James P., Ellinor, Patrick T., Busch-Nentwich, Elisabeth M., Ramirez-Solis, Ramiro, Murphy, Michael P., Persani, Luca, Bennett, Martin, Chatterjee, Krishna

المصدر: Schoenmakers , E , Marelli , F , Jørgensen , H F , Visser , W E , Moran , C , Groeneweg , S , Avalos , C , Jurgens , S J , Figg , N , Finigan , A , Wali , N , Agostini , M , Wardle-Jones , H , Lyons , G , Rusk , R , Gopalan , D , Twiss , P , Visser , J J , Goddard , M , Nashef , S A M , Heijmen , R , Clift , P , Sinha , S , Pirruccello ....

الوصف: Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient’s cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.

وصف الملف: application/pdf

العلاقة: https://pure.eur.nl/en/publications/da25ea95-adb5-4030-8a08-b20b13407cbfTest

الإتاحة: https://doi.org/10.1038/s41467-023-43851-6Test
https://pure.eur.nl/en/publications/da25ea95-adb5-4030-8a08-b20b13407cbfTest
https://pure.eur.nl/ws/files/121580676/Selenoprotein_deficiency_disorder_predisposes_to_aortic_aneurysm_formation.pdfTest
http://www.scopus.com/inward/record.url?scp=85178380449&partnerID=8YFLogxKTest

المؤلفون: Schoenmakers, Erik, Marelli, Federica, Jørgensen, Helle F., Visser, W. Edward, Moran, Carla, Groeneweg, Stefan, Avalos, Carolina, Jurgens, Sean J., Figg, Nichola, Finigan, Alison, Wali, Neha, Agostini, Maura, Wardle-Jones, Hannah, Lyons, Greta, Rusk, Rosemary, Gopalan, Deepa, Twiss, Philip, Visser, Jacob J., Goddard, Martin, Nashef, Samer A.M., Heijmen, Robin, Clift, Paul, Sinha, Sanjay, Pirruccello, James P., Ellinor, Patrick T., Busch-Nentwich, Elisabeth M., Ramirez-Solis, Ramiro, Murphy, Michael P., Persani, Luca, Bennett, Martin, Chatterjee, Krishna

المصدر: Schoenmakers , E , Marelli , F , Jørgensen , H F , Visser , W E , Moran , C , Groeneweg , S , Avalos , C , Jurgens , S J , Figg , N , Finigan , A , Wali , N , Agostini , M , Wardle-Jones , H , Lyons , G , Rusk , R , Gopalan , D , Twiss , P , Visser , J J , Goddard , M , Nashef , S A M , Heijmen , R , Clift , P , Sinha , S , Pirruccello ....

الوصف: Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient’s cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.

وصف الملف: application/pdf

العلاقة: https://pure.eur.nl/en/publications/da25ea95-adb5-4030-8a08-b20b13407cbfTest

الإتاحة: https://doi.org/10.1038/s41467-023-43851-6Test
https://pure.eur.nl/en/publications/da25ea95-adb5-4030-8a08-b20b13407cbfTest
https://pure.eur.nl/ws/files/121580676/Selenoprotein_deficiency_disorder_predisposes_to_aortic_aneurysm_formation.pdfTest
http://www.scopus.com/inward/record.url?scp=85178380449&partnerID=8YFLogxKTest

المؤلفون: Schoenmakers, Erik, Marelli, Federica, Jørgensen, Helle F, Visser, W Edward, Moran, Carla, Groeneweg, Stefan, Avalos, Carolina, Jurgens, Sean J, Figg, Nichola, Finigan, Alison, Wali, Neha, Agostini, Maura, Wardle-Jones, Hannah, Lyons, Greta, Rusk, Rosemary, Gopalan, Deepa, Twiss, Philip, Visser, Jacob J, Goddard, Martin, Nashef, Samer A M, Heijmen, Robin, Clift, Paul, Sinha, Sanjay, Pirruccello, James P, Ellinor, Patrick T, Busch-Nentwich, Elisabeth M, Ramirez-Solis, Ramiro, Murphy, Michael P, Persani, Luca, Bennett, Martin, Chatterjee, Krishna

المساهمون: E. Schoenmaker, F. Marelli, H.F. Jørgensen, W.E. Visser, C. Moran, S. Groeneweg, C. Avalo, S.J. Jurgen, N. Figg, A. Finigan, N. Wali, M. Agostini, H. Wardle-Jone, G. Lyon, R. Rusk, D. Gopalan, P. Twi, J.J. Visser, M. Goddard, S.A.M. Nashef, R. Heijmen, P. Clift, S. Sinha, J.P. Pirruccello, P.T. Ellinor, E.M. Busch-Nentwich, R. Ramirez-Soli, M.P. Murphy, L. Persani, M. Bennett, K. Chatterjee

مصطلحات موضوعية: Settore MED/13 - Endocrinologia, Settore MED/11 - Malattie dell'Apparato Cardiovascolare

الوصف: Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/38042913; volume:14; issue:1; firstpage:1; lastpage:14; numberofpages:14; journal:NATURE COMMUNICATIONS; https://hdl.handle.net/2434/1020410Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85178380449

الإتاحة: https://doi.org/10.1038/s41467-023-43851-6Test
https://hdl.handle.net/2434/1020410Test