Caroline J Coats1,2, Wendy E Heywood2, Alex Virasami3, Nadia Ashrafi2, Petros Syrris1, Cris Dos Remedios4, Thomas A Treibel1,5, James C Moon1,5, Luis R Lopes1,5, Christopher G A McGregor1, Michael Ashworth3, Neil J Sebire3, William J McKenna1, Kevin Mills2, Perry M Elliott1,5. 1. University College London Institute of Cardiovascular Science, London, United Kingdom (C.J.C., P.S., T.A.T., J.C.M., L.R.L., C.G.A.M., W.J.M., P.M.E.). 2. University College London Great Ormond Street Institute of Child Health, London, United Kingdom (C.J.C., W.E.H., N.A., K.M.). 3. Histopathology Unit, Great Ormond Street Hospital for Children, London, United Kingdom (A.V., M.A., N.J.S.). 4. Department of Anatomy and Histology, Bosch Institute, The University of Sydney, New South Wales, Australia (C.d.R.). 5. Barts Heart Centre, Barts Health NHS Trust, London, United Kingdom (T.A.T., J.C.M., L.R.L., P.M.E.).
Abstract
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by a complex phenotype that is only partly explained by the biological effects of individual genetic variants. The aim of this study was to use proteomic analysis of myocardial tissue to explore the postgenomic phenotype. METHODS: Label-free proteomic analysis was used initially to compare protein profiles in myocardial samples from 11 patients with HCM undergoing surgical myectomy with control samples from 6 healthy unused donor hearts. Differentially expressed proteins of interest were validated in myocardial samples from 65 unrelated individuals (HCM [n=51], controls [n=7], and aortic stenosis [n=7]) by the development and use of targeted multiple reaction monitoring-based triple quadrupole mass spectrometry. RESULTS: In this exploratory study, 1586 proteins were identified with 151 proteins differentially expressed in HCM samples compared with controls ( P<0.05). Protein expression profiling showed that many proteins identified in the initial discovery study were associated with metabolism, muscle contraction, calcium regulation, and oxidative stress. Proteins downregulated in HCM versus controls included creatine kinase M-type, fructose-bisphosphate aldolase A, and phosphoglycerate mutase ( P<0.001). Proteins upregulated in HCM included lumican, carbonic anhydrase 3, desmin, α-actin skeletal, and FHL1 (four and a half LIM domain protein 1; P<0.01). Myocardial lumican concentration correlated with the left atrial area (ρ=0.34, P=0.015), late gadolinium enhancement on cardiac magnetic resonance imaging ( P=0.03) and the presence of a pathogenic sarcomere mutation ( P=0.04). CONCLUSIONS: The myocardial proteome of HCM provides supporting evidence for dysregulation of metabolic and structural proteins. The finding that lumican is raised in HCM hearts provides insight into the myocardial fibrosis that characterizes this disease.
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by a complex phenotype that is only partly explained by the biological effects of individual genetic variants. The aim of this study was to use proteomic analysis of myocardial tissue to explore the postgenomic phenotype. METHODS: Label-free proteomic analysis was used initially to compare protein profiles in myocardial samples from 11 patients with HCM undergoing surgical myectomy with control samples from 6 healthy unused donor hearts. Differentially expressed proteins of interest were validated in myocardial samples from 65 unrelated individuals (HCM [n=51], controls [n=7], and aortic stenosis [n=7]) by the development and use of targeted multiple reaction monitoring-based triple quadrupole mass spectrometry. RESULTS: In this exploratory study, 1586 proteins were identified with 151 proteins differentially expressed in HCM samples compared with controls ( P<0.05). Protein expression profiling showed that many proteins identified in the initial discovery study were associated with metabolism, muscle contraction, calcium regulation, and oxidative stress. Proteins downregulated in HCM versus controls included creatine kinase M-type, fructose-bisphosphate aldolase A, and phosphoglycerate mutase ( P<0.001). Proteins upregulated in HCM included lumican, carbonic anhydrase 3, desmin, α-actin skeletal, and FHL1 (four and a half LIM domain protein 1; P<0.01). Myocardial lumican concentration correlated with the left atrial area (ρ=0.34, P=0.015), late gadolinium enhancement on cardiac magnetic resonance imaging ( P=0.03) and the presence of a pathogenic sarcomere mutation ( P=0.04). CONCLUSIONS: The myocardial proteome of HCM provides supporting evidence for dysregulation of metabolic and structural proteins. The finding that lumican is raised in HCM hearts provides insight into the myocardial fibrosis that characterizes this disease.
Authors: Gabriella Captur; Wendy E Heywood; Caroline Coats; Stefania Rosmini; Vimal Patel; Luis R Lopes; Richard Collis; Nina Patel; Petros Syrris; Paul Bassett; Ben O'Brien; James C Moon; Perry M Elliott; Kevin Mills Journal: Mol Cell Proteomics Date: 2019-06-26 Impact factor: 5.911
Authors: Bradley S Lander; Yanling Zhao; Kohei Hasegawa; Mathew S Maurer; Albree Tower-Rader; Michael A Fifer; Muredach P Reilly; Yuichi J Shimada Journal: Front Cardiovasc Med Date: 2022-06-17
Authors: Sara Ranjbarvaziri; Kristina B Kooiker; Mathew Ellenberger; Giovanni Fajardo; Mingming Zhao; Alison Schroer Vander Roest; Rahel A Woldeyes; Tiffany T Koyano; Robyn Fong; Ning Ma; Lei Tian; Gavin M Traber; Frandics Chan; John Perrino; Sushma Reddy; Wah Chiu; Joseph C Wu; Joseph Y Woo; Kathleen M Ruppel; James A Spudich; Michael P Snyder; Kévin Contrepois; Daniel Bernstein Journal: Circulation Date: 2021-10-21 Impact factor: 39.918
Authors: Larissa M Dorsch; Maike Schuldt; Cristobal G dos Remedios; Arend F L Schinkel; Peter L de Jong; Michelle Michels; Diederik W D Kuster; Bianca J J M Brundel; Jolanda van der Velden Journal: Cells Date: 2019-07-18 Impact factor: 6.600
Authors: Jolanda van der Velden; Diederik W D Kuster; Maike Schuldt; Jiayi Pei; Magdalena Harakalova; Larissa M Dorsch; Saskia Schlossarek; Michal Mokry; Jaco C Knol; Thang V Pham; Tim Schelfhorst; Sander R Piersma; Cris Dos Remedios; Michiel Dalinghaus; Michelle Michels; Folkert W Asselbergs; Marie-Jo Moutin; Lucie Carrier; Connie R Jimenez Journal: Circ Heart Fail Date: 2021-01-12 Impact factor: 8.790
Authors: Maike Schuldt; Larissa M Dorsch; Jaco C Knol; Thang V Pham; Tim Schelfhorst; Sander R Piersma; Cris Dos Remedios; Michelle Michels; Connie R Jimenez; Diederik W D Kuster; Jolanda van der Velden Journal: Front Cardiovasc Med Date: 2021-03-01
Authors: Mengbo Li; Benjamin L Parker; Evangeline Pearson; Benjamin Hunter; Jacob Cao; Yen Chin Koay; Oneka Guneratne; David E James; Jean Yang; Sean Lal; John F O'Sullivan Journal: Nat Commun Date: 2020-06-02 Impact factor: 14.919