Neutrophil peptidylarginine deiminase 4 is essential for detrimental age-related cardiac remodelling and dysfunction in mice.

Autor:	Van Bruggen S; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, O&N1 Herestraat 49 - Bus 911, 3000 Leuven, Belgium., Kraisin S; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, O&N1 Herestraat 49 - Bus 911, 3000 Leuven, Belgium., Van Wauwe J; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, O&N1 Herestraat 49 - Bus 911, 3000 Leuven, Belgium., Bomhals K; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, O&N1 Herestraat 49 - Bus 911, 3000 Leuven, Belgium., Stroobants M; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, O&N1 Herestraat 49 - Bus 911, 3000 Leuven, Belgium., Carai P; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, O&N1 Herestraat 49 - Bus 911, 3000 Leuven, Belgium., Frederix L; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, O&N1 Herestraat 49 - Bus 911, 3000 Leuven, Belgium., Van De Bruaene A; Division of Cardiology, Department of Cardiovascular Sciences, KU Leuven, KU Leuven, Leuven 3000, Belgium.; Division of Structural and Congenital Cardiology, University Hospitals Leuven, Leuven 3000, Belgium., Witsch T; Department of Cardiology and Angiology I, University of Freiburg, Heart Center, Faculty of Medicine, University of Freiburg, Freiburg 79110, Germany., Martinod K; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, O&N1 Herestraat 49 - Bus 911, 3000 Leuven, Belgium.
Jazyk:	angličtina
Zdroj:	Philosophical transactions of the Royal Society of London. Series B, Biological sciences [Philos Trans R Soc Lond B Biol Sci] 2023 Nov 20; Vol. 378 (1890), pp. 20220475. Date of Electronic Publication: 2023 Oct 02.
DOI:	10.1098/rstb.2022.0475
Abstrakt:	Mice fully deficient in peptidylarginine deiminase 4 (PAD4) enzyme have preserved cardiac function and reduced collagen deposition during ageing. The cellular source of PAD4 is hypothesized to be neutrophils, likely due to PAD4's involvement in neutrophil extracellular trap release. We investigated haematopoietic PAD4 impact on myocardial remodelling and systemic inflammation in cardiac ageing by generating mice with Padi4 deletion in circulating neutrophils under the MRP8 promoter (Ne-PAD4 -/- ), and ageing them for 2 years together with littermate controls (PAD4 fl/fl ). Ne-PAD4 -/- mice showed protection against age-induced fibrosis, seen by reduced cardiac collagen deposition. Echocardiography analysis of structural and functional parameters also demonstrated preservation of both systolic and diastolic function with MRP8-driven PAD4 deletion. Furthermore, cardiac gene expression and plasma cytokine levels were evaluated. Cardiac genes and plasma cytokines involved in neutrophil recruitment were downregulated in aged Ne-PAD4 -/- animals compared to PAD4 fl/fl controls, including decreased levels of C-X-C ligand 1 (CXCL1). Our data confirm PAD4 involvement from circulating neutrophils in detrimental cardiac remodelling, leading to cardiac dysfunction with old age. Deletion of PAD4 in MRP8-expressing cells impacts the CXCL1-CXCR2 axis, known to be involved in heart failure development. This supports the future use of PAD4 inhibitors in cardiovascular disease. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.
Databáze:	MEDLINE
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