Annie Turkieh1, Marie Fertin1, Marion Bouvet1, Paul Mulder2, Hervé Drobecq3, Gilles Lemesle4,5,6, Nicolas Lamblin1,4,5,6, Pascal de Groote1,4, Sina Porouchani1, Maggy Chwastyniak1, Olivia Beseme1, Philippe Amouyel1,5,7, Frédéric Mouquet4, Jean-Luc Balligand8, Vincent Richard2, Christophe Bauters1,4,5,6, Florence Pinet9. 1. INSERM U1167-RID-AGE, CHU Lille, FHU-REMOD-VHF (A.T., M.F., M.B., N.L., P.d.G., S.P., M.C., O.B., P.A., C.B., F.P.). 2. Institut Pasteur de Lille, Université de Lille, France. Inserm U1096, FHU-REMOD-VHF, Normandie University, University of Rouen, France (P.M., V.R.). 3. UMR 8161-M3T-Mechanisms of Tumorigenesis and Target Therapies, CNRS (H.D.). 4. USIC et Centre Hémodynamique, Institut Coeur Poumon, Centre Hospitalier Régional et Universitaire de Lille, France (G.L., N.L., P.d.G., F.M., C.B.). 5. Faculté de Médecine de l'Université de Lille, France (G.L., N.L., P.A., C.B.). 6. FACT, French Alliance for Cardiovascular Trials, Paris, France (G.L., N.L., C.B.). 7. CHU Lille, Service de Santé Publique, Épidémiologie, Économie de la Santé et Prévention, France (P.A.). 8. Institut de Recherche Experimentale et Clinique, Pole of Pharmacology and Therapeutics and Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium (J.-L.B.). 9. INSERM U1167-RID-AGE, CHU Lille, FHU-REMOD-VHF (A.T., M.F., M.B., N.L., P.d.G., S.P., M.C., O.B., P.A., C.B., F.P.) florence.pinet@pasteur-lille.fr.
Abstract
BACKGROUND: Left ventricular remodeling (LVR) after myocardial infarction is associated with an increased risk of heart failure and death. In spite of a modern therapeutic approach, LVR remains relatively frequent and difficult to predict in clinical practice. Our aim was to identify new biomarkers of LVR and understand their involvement in its development. METHODS AND RESULTS: Proteomic analysis of plasma from the REVE-2 study (Remodelage Ventriculaire)-a study dedicated to the analysis of LVR which included 246 patients after a first anterior myocardial infarction-identified increased plasma levels of CLU (clusterin) in patients with high LVR. We used a rat model of myocardial infarction to analyze CLU expression in the LV and found a significant increase that was correlated with LVR parameters. We found increased CLU expression and secretion in primary cultures of rat neonate cardiomyocytes hypertrophied by isoproterenol. Silencing of CLU in hypertrophied neonate cardiomyocytes induced a significant decrease in cell size, ANP (atrial natriuretic peptide), and BNP (B-type natriuretic peptide) expression, associated with a decreased ERK (extracellular signal-regulated kinase) 1/2 activity, suggesting a prohypertrophic role of CLU. We then confirmed a significant increase of both intracellular p-CLU (precursor form of CLU) and m-CLU (mature form of CLU) in failing human hearts. Finally, the circulating levels of CLU (secreted form) were increased in patients with chronic heart failure who died from cardiovascular cause during a 3-year follow-up (n=99) compared with survivors (n=99). CONCLUSIONS: Our results show for the first time that plasma CLU levels are associated with LVR post-myocardial infarction, have in part a cardiac origin, and are a predictor of early death in heart failure patients.
BACKGROUND:Left ventricular remodeling (LVR) after myocardial infarction is associated with an increased risk of heart failure and death. In spite of a modern therapeutic approach, LVR remains relatively frequent and difficult to predict in clinical practice. Our aim was to identify new biomarkers of LVR and understand their involvement in its development. METHODS AND RESULTS: Proteomic analysis of plasma from the REVE-2 study (Remodelage Ventriculaire)-a study dedicated to the analysis of LVR which included 246 patients after a first anterior myocardial infarction-identified increased plasma levels of CLU (clusterin) in patients with high LVR. We used a rat model of myocardial infarction to analyze CLU expression in the LV and found a significant increase that was correlated with LVR parameters. We found increased CLU expression and secretion in primary cultures of rat neonate cardiomyocytes hypertrophied by isoproterenol. Silencing of CLU in hypertrophied neonate cardiomyocytes induced a significant decrease in cell size, ANP (atrial natriuretic peptide), and BNP (B-type natriuretic peptide) expression, associated with a decreased ERK (extracellular signal-regulated kinase) 1/2 activity, suggesting a prohypertrophic role of CLU. We then confirmed a significant increase of both intracellular p-CLU (precursor form of CLU) and m-CLU (mature form of CLU) in failing human hearts. Finally, the circulating levels of CLU (secreted form) were increased in patients with chronic heart failure who died from cardiovascular cause during a 3-year follow-up (n=99) compared with survivors (n=99). CONCLUSIONS: Our results show for the first time that plasma CLU levels are associated with LVR post-myocardial infarction, have in part a cardiac origin, and are a predictor of early death in heart failurepatients.
Authors: Manuel Teixeira; Dário Trindade; Marisol Gouveia; Roberta Eller-Borges; Sandra Magalhães; Ana Duarte; Miriam Ferreira; Maria I Simões; Maria Conceição; Alexandra Nunes; Ana Gabriela Henriques; Fernando Ribeiro; Sandra I Vieira Journal: Cells Date: 2022-05-19 Impact factor: 7.666
Authors: Denise Traxler; Andreas Spannbauer; Patrick Einzinger; Julia Mester-Tonczar; Dominika Lukovic; Johannes Winkler; Katrin Zlabinger; Alfred Gugerell; LJubica Mandic; Mariann Gyöngyösi; Noemi Pavo Journal: Int J Mol Sci Date: 2020-06-28 Impact factor: 5.923
Authors: Dominik Jenča; Vojtěch Melenovský; Josef Stehlik; Vladimír Staněk; Jiří Kettner; Josef Kautzner; Věra Adámková; Peter Wohlfahrt Journal: ESC Heart Fail Date: 2020-12-14