Evidence map›Paper›PMID 39421928›Full record

ArticleCirculation research2024

Shear-Sensing by C-Reactive Protein: Linking Aortic Stenosis and Inflammation.

Johannes Zeller, Julia Loseff-Silver, Khashayar Khoshmanesh, Sara Baratchi, Austin Lai, Tracy L Nero, Abhishek Roy, Anna Watson, Nalin Dayawansa, Prerna Sharma and 21 more

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Article in Circulation research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.

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16citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

Who cites it

16 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

31 authors.

Johannes ZellerAtherothrombosis 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.).ORCID 0000-0002-8122-9063
Julia Loseff-SilverAtherothrombosis 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.).ORCID 0000-0002-1570-556X
Khashayar KhoshmaneshSchool of Engineering, RMIT University, Melbourne, Victoria, Australia (K.K.).ORCID 0000-0001-6036-7371
Sara BaratchiAtherothrombosis 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.).ORCID 0000-0003-3588-7951
Austin LaiAtherothrombosis 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.).ORCID 0009-0003-6208-5660
Tracy L NeroDepartment 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.ORCID 0000-0002-3393-1843
Abhishek RoyAtherothrombosis 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.).
Anna WatsonAtherothrombosis 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.).
Nalin DayawansaAtherothrombosis 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.).ORCID 0000-0002-1863-092X
Prerna SharmaAtherothrombosis 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.).ORCID 0009-0007-6878-7240
Anastasia Barbaro-WahlAtherothrombosis 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.).ORCID 0009-0001-1058-7824
Yung Chih ChenAtherothrombosis 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.).ORCID 0000-0002-5387-5818
Mitchell MoonAtherothrombosis 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.).ORCID 0000-0001-9345-5001
Mark Louis P VidallonAtherothrombosis 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.).ORCID 0000-0002-0026-3906
Angela HuangAtherothrombosis 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.).
Julia ThomeDepartment of Plastic and Hand Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Breisgau, Germany (J.Z., J.T., D.B., S.U.E.).ORCID 0000-0002-1962-9525
Karen S Cheung Tung ShingDepartment 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.
Dalton HarvieDepartment of Chemical Engineering (D.H., M.N.B.), Clayton, Victoria, Australia.ORCID 0000-0002-8501-1344
Marie N BongiovanniDepartment of Chemical Engineering (D.H., M.N.B.), Clayton, Victoria, Australia.
David BraigDepartment of Plastic and Hand Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Breisgau, Germany (J.Z., J.T., D.B., S.U.E.).ORCID 0000-0002-1267-0840
Craig J MortonDepartment 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.ORCID 0000-0001-5452-5193
Nay M HtunAtherothrombosis 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.).
Dion StubDepartment of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia (N.D., N.M.H., D.S., A. Walton, K.P.).ORCID 0000-0001-8686-2709
Anthony WaltonDepartment of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia (N.D., N.M.H., D.S., A. Walton, K.P.).ORCID 0000-0002-9173-5904
John HorowitzDepartment of Cardiology, Queen Elizabeth Hospital, Adelaide, South Australia, Australia (J.H.).ORCID 0000-0001-6883-0703
Xiaowei WangAtherothrombosis 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.).ORCID 0000-0001-8658-7399
Geoffrey PieterszAtherothrombosis 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.).ORCID 0000-0002-1999-6835
Michael W ParkerDepartment 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.ORCID 0000-0002-3101-1138
Steffen U EisenhardtDepartment of Plastic and Hand Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Breisgau, Germany (J.Z., J.T., D.B., S.U.E.).ORCID 0000-0003-4471-3160
James D McFadyen *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.).ORCID 0000-0002-9832-6871
Karlheinz Peter *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.).ORCID 0000-0002-8040-2258

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundCRP (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.

methodsTo 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.

resultsExposed 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-β (transforming growth factor beta) expression on platelets.

conclusionsWe 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.

Indexed as

Aortic Valve StenosisC-Reactive ProteinInflammationAgedAnimalsAortic ValveFemaleHumansMaleMiceMice, Inbred C57BLStress, MechanicalTranscatheter Aortic Valve ReplacementC-Reactive Proteinaortic valve stenosisC-reactive proteininflammationproteolysisthrombosis

Identifiers

PMID39421928
PMCPMC11542976

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