Diego Martínez-López1, Raquel Roldan-Montero1, Fernando García-Marqués2, Estefania Nuñez2, Inmaculada Jorge2, Emilio Camafeita2, Pablo Minguez3, Santiago Rodriguez de Cordoba4, Beatriz López-Melgar5, Enrique Lara-Pezzi2, Antonio Fernández-Ortiz6, Borja Ibáñez7, Jose Manuel Valdivielso8, Valentín Fuster9, Jean-Baptiste Michel10, Luis Miguel Blanco-Colio1, Jesús Vázquez11, Jose Luis Martin-Ventura12. 1. IIS-Fundación Jiménez Díaz-Universidad Autónoma, and CIBERCV, Madrid, Spain. 2. Centro Nacional de Investigaciones Cardiovasculares (CNIC) and CIBERCV, Madrid, Spain. 3. IIS-Fundación Jiménez Díaz-Universidad Autónoma, and CIBERER, Madrid, Spain. 4. Centro de Investigaciones Biologicas and Ciber de Enfermedades Raras, Madrid, Spain. 5. Centro Nacional de Investigaciones Cardiovasculares (CNIC) and CIBERCV, Madrid, Spain; Hospital Universitario HM Montepríncipe-CIEC and Universidad CEU San Pablo, Madrid, Spain. 6. Centro Nacional de Investigaciones Cardiovasculares (CNIC) and CIBERCV, Madrid, Spain; Hospital Clínico San Carlos, Universidad Complutense, IdISSC, Madrid, Spain. 7. IIS-Fundación Jiménez Díaz-Universidad Autónoma, and CIBERCV, Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares (CNIC) and CIBERCV, Madrid, Spain. 8. Vascular and Renal Translational Research Group, IRBLLEIDA, Lleida, Spain. 9. Centro Nacional de Investigaciones Cardiovasculares (CNIC) and CIBERCV, Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York. 10. INSERM U1148 X. Bichat hospital, 75018 Paris, Paris, France. 11. Centro Nacional de Investigaciones Cardiovasculares (CNIC) and CIBERCV, Madrid, Spain. Electronic address: jvazquez@cnic.es. 12. IIS-Fundación Jiménez Díaz-Universidad Autónoma, and CIBERCV, Madrid, Spain. Electronic address: jlmartin@fjd.es.
Abstract
BACKGROUND: The mechanisms underlying early atherosclerotic plaque formation are not completely understood. Moreover, plasma biomarkers of subclinical atherosclerosis are lacking. OBJECTIVES: The purpose of this study was to analyze the temporal and topologically resolved protein changes taking place in human aortas with early atherosclerosis to find new potential diagnostic and/or therapeutic targets. METHODS: The protein composition of healthy aortas (media layer) or with early atheroma (fatty streak and fibrolipidic, media and intima layers) was analyzed by deep quantitative multiplexed proteomics. Further analysis was performed by Western blot, immunohistochemistry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. Plasma levels of complement C5 were analyzed in relation to the presence of generalized (>2 plaques) or incipient (0 to 2 plaques) subclinical atherosclerosis in 2 independent clinical cohorts (PESA [Progression of Early Subclinical Atherosclerosis] [n = 360] and NEFRONA [National Observatory of Atherosclerosis in Nephrology] [n = 394]). RESULTS: Proteins involved in lipid transport, complement system, immunoglobulin superfamily, and hemostasis are increased in early plaques. Components from the complement activation pathway were predominantly increased in the intima of fibrolipidic plaques. Among them, increased C5 protein levels were further confirmed by Western blot, enzyme-linked immunosorbent assay and immunohistochemistry, and associated with in situ complement activation. Plasma C5 was significantly increased in individuals with generalized subclinical atherosclerosis in both PESA and NEFRONA cohorts, independently of risk factors. Moreover, in the PESA study, C5 plasma levels positively correlated with global plaque volume and coronary calcification. CONCLUSIONS: Activation of the complement system is a major alteration in early atherosclerotic plaques and is reflected by increased C5 plasma levels, which have promising value as a novel circulating biomarker of subclinical atherosclerosis.
BACKGROUND: The mechanisms underlying early atherosclerotic plaque formation are not completely understood. Moreover, plasma biomarkers of subclinical atherosclerosis are lacking. OBJECTIVES: The purpose of this study was to analyze the temporal and topologically resolved protein changes taking place in human aortas with early atherosclerosis to find new potential diagnostic and/or therapeutic targets. METHODS: The protein composition of healthy aortas (media layer) or with early atheroma (fatty streak and fibrolipidic, media and intima layers) was analyzed by deep quantitative multiplexed proteomics. Further analysis was performed by Western blot, immunohistochemistry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. Plasma levels of complement C5 were analyzed in relation to the presence of generalized (>2 plaques) or incipient (0 to 2 plaques) subclinical atherosclerosis in 2 independent clinical cohorts (PESA [Progression of Early Subclinical Atherosclerosis] [n = 360] and NEFRONA [National Observatory of Atherosclerosis in Nephrology] [n = 394]). RESULTS: Proteins involved in lipid transport, complement system, immunoglobulin superfamily, and hemostasis are increased in early plaques. Components from the complement activation pathway were predominantly increased in the intima of fibrolipidic plaques. Among them, increased C5 protein levels were further confirmed by Western blot, enzyme-linked immunosorbent assay and immunohistochemistry, and associated with in situ complement activation. Plasma C5 was significantly increased in individuals with generalized subclinical atherosclerosis in both PESA and NEFRONA cohorts, independently of risk factors. Moreover, in the PESA study, C5 plasma levels positively correlated with global plaque volume and coronary calcification. CONCLUSIONS: Activation of the complement system is a major alteration in early atherosclerotic plaques and is reflected by increased C5 plasma levels, which have promising value as a novel circulating biomarker of subclinical atherosclerosis.
Authors: Ivan Vujkovic-Cvijin; Ornella Sortino; Eveline Verheij; Ferdinand W Wit; Neeltje A Kootstra; Brian Sellers; Maarten Schim van der Loeff; Yasmine Belkaid; Peter Reiss; Irini Sereti Journal: J Infect Dis Date: 2021-10-28 Impact factor: 5.226
Authors: Pradeep Natarajan; Karen N Conneely; M D Mesbah Uddin; Ngoc Quynh H Nguyen; Bing Yu; Jennifer A Brody; Akhil Pampana; Tetsushi Nakao; Myriam Fornage; Jan Bressler; Nona Sotoodehnia; Joshua S Weinstock; Michael C Honigberg; Daniel Nachun; Romit Bhattacharya; Gabriel K Griffin; Varuna Chander; Richard A Gibbs; Jerome I Rotter; Chunyu Liu; Andrea A Baccarelli; Daniel I Chasman; Eric A Whitsel; Douglas P Kiel; Joanne M Murabito; Eric Boerwinkle; Benjamin L Ebert; Siddhartha Jaiswal; James S Floyd; Alexander G Bick; Christie M Ballantyne; Bruce M Psaty Journal: Nat Commun Date: 2022-09-12 Impact factor: 17.694
Authors: Jessica Kristin Henes; Patrick Groga-Bada; Elke Schaeffeler; Stefan Winter; Luis Hack; Monika Zdanyte; Karin Mueller; Michal Droppa; Fabian Stimpfle; Meinrad Gawaz; Harald Langer; Matthias Schwab; Tobias Geisler; Dominik Rath Journal: Pharmgenomics Pers Med Date: 2021-07-21