{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:10:55Z","timestamp":1791360655592,"version":"4.3.1"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","license":[{"start":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T00:00:00Z","timestamp":1731024000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,11,8]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>CRP (C-reactive protein) is a prototypical acute phase reactant. Upon dissociation of the pentameric isoform (pCRP [pentameric CRP]) into its monomeric subunits (mCRP [monomeric CRP]), it exhibits prothrombotic and proinflammatory activity. Pathophysiological shear rates as observed in aortic valve stenosis (AS) can influence protein conformation and function as observed with vWF (von Willebrand factor). Given the proinflammatory function of dissociated CRP and the important role of inflammation in the pathogenesis of AS, we investigated whether shear stress can modify CRP conformation and induce inflammatory effects relevant to AS.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>To determine the effects of pathological shear rates on the function of human CRP, pCRP was subjected to pathophysiologically relevant shear rates and analyzed using biophysical and biochemical methods. To investigate the effect of shear on CRP conformation in vivo, we used a mouse model of arterial stenosis. Levels of mCRP and pCRP were measured in patients with severe AS pre- and post-transcatheter aortic valve implantation, and the presence of CRP was investigated on excised valves from patients undergoing aortic valve replacement surgery for severe AS. Microfluidic models of AS were then used to recapitulate the shear rates of patients with AS and to investigate this shear-dependent dissociation of pCRP and its inflammatory function.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>Exposed to high shear rates, pCRP dissociates into its proinflammatory monomers (mCRP) and aggregates into large particles. Our in vitro findings were further confirmed in a mouse carotid artery stenosis model, where the administration of human pCRP led to the deposition of mCRP poststenosis. Patients undergoing transcatheter aortic valve implantation demonstrated significantly higher mCRP bound to circulating microvesicles pre-transcatheter aortic valve implantation compared with post-transcatheter aortic valve implantation. Excised human stenotic aortic valves display mCRP deposition. pCRP dissociated in a microfluidic model of AS and induces endothelial cell activation as measured by increased ICAM-1 (intercellular adhesion molecule 1) and P-selectin expression. mCRP also induces platelet activation and TGF-\u03b2 (transforming growth factor beta) expression on platelets.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>We identify a novel mechanism of shear-induced pCRP dissociation, which results in the activation of cells central to the development of AS. This novel mechanosensing mechanism of pCRP dissociation to mCRP is likely also relevant to other pathologies involving increased shear rates, such as in atherosclerotic and injured arteries.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.124.324248","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T09:00:27Z","timestamp":1729242027000},"page":"1033-1047","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Shear-Sensing by C-Reactive Protein: Linking Aortic Stenosis and Inflammation"],"prefix":"10.1161","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8122-9063","authenticated-orcid":true,"given":"Johannes","family":"Zeller","sequence":"first","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."},{"name":"Department of Plastic and Hand Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Breisgau, Germany (J.Z., J.T., D.B., S.U.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1570-556X","authenticated-orcid":true,"given":"Julia","family":"Loseff-Silver","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6036-7371","authenticated-orcid":true,"given":"Khashayar","family":"Khoshmanesh","sequence":"additional","affiliation":[{"name":"School of Engineering, RMIT University, Melbourne, Victoria, Australia (K.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3588-7951","authenticated-orcid":true,"given":"Sara","family":"Baratchi","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."},{"name":"Department of Cardiometabolic Health (S.B., T.L.N., A.R., M.M., M.L.P.V., K.S.C.T.S., C.J.M., X.W., M.W.P., J.D.M., K.P.), Clayton, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6208-5660","authenticated-orcid":true,"given":"Austin","family":"Lai","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3393-1843","authenticated-orcid":true,"given":"Tracy L.","family":"Nero","sequence":"additional","affiliation":[{"name":"Department of Cardiometabolic Health (S.B., T.L.N., A.R., M.M., M.L.P.V., K.S.C.T.S., C.J.M., X.W., M.W.P., J.D.M., K.P.), Clayton, Victoria, Australia."},{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute (T.L.N., K.S.C.T.S., C.J.M., M.W.P.), Clayton, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Roy","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."},{"name":"Department of Cardiometabolic Health (S.B., T.L.N., A.R., M.M., M.L.P.V., K.S.C.T.S., C.J.M., X.W., M.W.P., J.D.M., K.P.), Clayton, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Watson","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1863-092X","authenticated-orcid":true,"given":"Nalin","family":"Dayawansa","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."},{"name":"Department of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia (N.D., N.M.H., D.S., A. Walton, K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6878-7240","authenticated-orcid":true,"given":"Prerna","family":"Sharma","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1058-7824","authenticated-orcid":true,"given":"Anastasia","family":"Barbaro-Wahl","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5387-5818","authenticated-orcid":true,"given":"Yung Chih","family":"Chen","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9345-5001","authenticated-orcid":true,"given":"Mitchell","family":"Moon","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."},{"name":"Department of Cardiometabolic Health (S.B., T.L.N., A.R., M.M., M.L.P.V., K.S.C.T.S., C.J.M., X.W., M.W.P., J.D.M., K.P.), Clayton, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0026-3906","authenticated-orcid":true,"given":"Mark Louis P.","family":"Vidallon","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."},{"name":"Department of Cardiometabolic Health (S.B., T.L.N., A.R., M.M., M.L.P.V., K.S.C.T.S., C.J.M., X.W., M.W.P., J.D.M., K.P.), Clayton, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Huang","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1962-9525","authenticated-orcid":true,"given":"Julia","family":"Thome","sequence":"additional","affiliation":[{"name":"Department of Plastic and Hand Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Breisgau, Germany (J.Z., J.T., D.B., S.U.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen S.","family":"Cheung Tung Shing","sequence":"additional","affiliation":[{"name":"Department of Cardiometabolic Health (S.B., T.L.N., A.R., M.M., M.L.P.V., K.S.C.T.S., C.J.M., X.W., M.W.P., J.D.M., K.P.), Clayton, Victoria, Australia."},{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute (T.L.N., K.S.C.T.S., C.J.M., M.W.P.), Clayton, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8501-1344","authenticated-orcid":true,"given":"Dalton","family":"Harvie","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering (D.H., M.N.B.), Clayton, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie N.","family":"Bongiovanni","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering (D.H., M.N.B.), Clayton, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1267-0840","authenticated-orcid":true,"given":"David","family":"Braig","sequence":"additional","affiliation":[{"name":"Department of Plastic and Hand Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Breisgau, Germany (J.Z., J.T., D.B., S.U.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5452-5193","authenticated-orcid":true,"given":"Craig J.","family":"Morton","sequence":"additional","affiliation":[{"name":"Department of Cardiometabolic Health (S.B., T.L.N., A.R., M.M., M.L.P.V., K.S.C.T.S., C.J.M., X.W., M.W.P., J.D.M., K.P.), Clayton, Victoria, Australia."},{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute (T.L.N., K.S.C.T.S., C.J.M., M.W.P.), Clayton, Victoria, Australia."},{"name":"The University of Melbourne, Parkville, Victoria, Australia; now with CSIRO Biomedical Manufacturing, Clayton, Victoria, Australia (C.J.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nay M.","family":"Htun","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."},{"name":"Department of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia (N.D., N.M.H., D.S., A. Walton, K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8686-2709","authenticated-orcid":true,"given":"Dion","family":"Stub","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia (N.D., N.M.H., D.S., A. Walton, K.P.)."},{"name":"Department of Epidemiology and Preventive Medicine (D.S.), Melbourne, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9173-5904","authenticated-orcid":true,"given":"Anthony","family":"Walton","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia (N.D., N.M.H., D.S., A. Walton, K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6883-0703","authenticated-orcid":true,"given":"John","family":"Horowitz","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Queen Elizabeth Hospital, Adelaide, South Australia, Australia (J.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8658-7399","authenticated-orcid":true,"given":"Xiaowei","family":"Wang","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."},{"name":"Department of Cardiometabolic Health (S.B., T.L.N., A.R., M.M., M.L.P.V., K.S.C.T.S., C.J.M., X.W., M.W.P., J.D.M., K.P.), Clayton, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1999-6835","authenticated-orcid":true,"given":"Geoffrey","family":"Pietersz","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3101-1138","authenticated-orcid":true,"given":"Michael W.","family":"Parker","sequence":"additional","affiliation":[{"name":"Department of Cardiometabolic Health (S.B., T.L.N., A.R., M.M., M.L.P.V., K.S.C.T.S., C.J.M., X.W., M.W.P., J.D.M., K.P.), Clayton, Victoria, Australia."},{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute (T.L.N., K.S.C.T.S., C.J.M., M.W.P.), Clayton, Victoria, Australia."},{"name":"ACRF Rational Drug Discovery Centre, St Vincent\u2019s Institute of Medical Research, Fitzroy, Victoria, Australia (M.W.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4471-3160","authenticated-orcid":true,"given":"Steffen U.","family":"Eisenhardt","sequence":"additional","affiliation":[{"name":"Department of Plastic and Hand Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Breisgau, Germany (J.Z., J.T., D.B., S.U.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9832-6871","authenticated-orcid":true,"given":"James D.","family":"McFadyen","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.)."},{"name":"Department of Cardiometabolic Health (S.B., T.L.N., A.R., M.M., M.L.P.V., K.S.C.T.S., C.J.M., X.W., M.W.P., J.D.M., K.P.), Clayton, Victoria, Australia."},{"name":"Department of Clinical Haematology (J.D.M), School of Translational Medicine Monash University, Melbourne, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8040-2258","authenticated-orcid":true,"given":"Karlheinz","family":"Peter","sequence":"additional","affiliation":[{"name":"Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. 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