Reindert W Emmens1, Umit Baylan2, Lynda J M Juffermans3, Rashmi V Karia4, Bauke Ylstra5, Diana Wouters6, Sacha Zeerleder7, Suat Simsek8, Marieke van Ham9, Hans W M Niessen10, Paul A J Krijnen11. 1. Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; Department of Immunopathology, Sanquin Research, Postbus 9892, 1006 AN, Amsterdam, The Netherlands. Electronic address: r.emmens@vumc.nl. 2. Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. Electronic address: u.baylan@vumc.nl. 3. Department of Cardiology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; Interuniversity Cardiology Institute of The Netherlands, Postbus 19258, 3501 DG, Utrecht, The Netherlands. Electronic address: ljm.juffermans@vumc.nl. 4. Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. Electronic address: rashmi.v.karia@gmail.com. 5. Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. Electronic address: b.ylstra@vumc.nl. 6. Department of Immunopathology, Sanquin Research, Postbus 9892, 1006 AN, Amsterdam, The Netherlands. Electronic address: d.wouters@sanquin.nl. 7. Department of Immunopathology, Sanquin Research, Postbus 9892, 1006 AN, Amsterdam, The Netherlands; Department of Hematology, Academic Medical Center, Postbus 22660, 1100 AD, Amsterdam, The Netherlands. Electronic address: s.s.zeerleder@amc.uva.nl. 8. Department of Internal Medicine, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; Department of Internal Medicine, Medical Center Alkmaar, Postbus 501, 1800 AM, Alkmaar, The Netherlands. Electronic address: s.simsek@mca.nl. 9. Department of Immunopathology, Sanquin Research, Postbus 9892, 1006 AN, Amsterdam, The Netherlands. Electronic address: m.vanham@sanquin.nl. 10. Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; Department of Cardiac Surgery, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. Electronic address: jwm.niessen@vumc.nl. 11. Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. Electronic address: paj.krijnen@vumc.nl.
Abstract
BACKGROUND: Complement activation contributes significantly to inflammation-related damage in the heart after acute myocardial infarction. Knowledge on factors that regulate postinfraction complement activation is incomplete however. In this study, we investigated whether endogenous C1-inhibitor, a well-known inhibitor of complement activation, is expressed in the heart after acute myocardial infarction. MATERIALS AND METHODS: C1-inhibitor and complement activation products C3d and C4d were analyzed immunohistochemically in the hearts of patients who died at different time intervals after acute myocardial infarction (n=28) and of control patients (n=8). To determine putative local C1-inhibitor production, cardiac transcript levels of the C1-inhibitor-encoding gene serping1 were determined in rats after induction of acute myocardial infarction (microarray). Additionally, C1-inhibitor expression was analyzed (fluorescence microscopy) in human endothelial cells and rat cardiomyoblasts in vitro. RESULTS: C1-inhibitor was found predominantly in and on jeopardized cardiomyocytes in necrotic infarct cores between 12h and 5days old. C1-inhibitor protein expression coincided in time and colocalized with C3d and C4d. In the rat heart, serping1 transcript levels were increased from 2h up until 7days after acute myocardial infarction. Both endothelial cells and cardiomyoblasts showed increased intracellular expression of C1-inhibitor in response to ischemia in vitro (n=4). CONCLUSIONS: These observations suggest that endogenous C1-inhibitor is likely involved in the regulation of complement activity in the myocardium following acute myocardial infarction. Observations in rat and in vitro suggest that C1-inhibitor is produced locally in the heart after acute myocardial infarction.
BACKGROUND: Complement activation contributes significantly to inflammation-related damage in the heart after acute myocardial infarction. Knowledge on factors that regulate postinfraction complement activation is incomplete however. In this study, we investigated whether endogenous C1-inhibitor, a well-known inhibitor of complement activation, is expressed in the heart after acute myocardial infarction. MATERIALS AND METHODS: C1-inhibitor and complement activation products C3d and C4d were analyzed immunohistochemically in the hearts of patients who died at different time intervals after acute myocardial infarction (n=28) and of control patients (n=8). To determine putative local C1-inhibitor production, cardiac transcript levels of the C1-inhibitor-encoding gene serping1 were determined in rats after induction of acute myocardial infarction (microarray). Additionally, C1-inhibitor expression was analyzed (fluorescence microscopy) in human endothelial cells and rat cardiomyoblasts in vitro. RESULTS: C1-inhibitor was found predominantly in and on jeopardized cardiomyocytes in necrotic infarct cores between 12h and 5days old. C1-inhibitor protein expression coincided in time and colocalized with C3d and C4d. In the rat heart, serping1 transcript levels were increased from 2h up until 7days after acute myocardial infarction. Both endothelial cells and cardiomyoblasts showed increased intracellular expression of C1-inhibitor in response to ischemia in vitro (n=4). CONCLUSIONS: These observations suggest that endogenous C1-inhibitor is likely involved in the regulation of complement activity in the myocardium following acute myocardial infarction. Observations in rat and in vitro suggest that C1-inhibitor is produced locally in the heart after acute myocardial infarction.
Authors: Ya-Nan Zhang; Flora Vernooij; Irwani Ibrahim; Shirley Ooi; Crystel M Gijsberts; Arjan H Schoneveld; Kuan Win Sen; Hester M den Ruijter; Leo Timmers; Arthur Mark Richards; Chun Tzen Jong; Ibrahim Mazlan; Jiong-Wei Wang; Carolyn S P Lam; Dominique P V de Kleijn Journal: PLoS One Date: 2016-01-28 Impact factor: 3.240