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Title: Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure.
Austin Authors: Marques, Francine Z;Prestes, Priscilla R;Byars, Sean G;Ritchie, Scott C;Würtz, Peter;Patel, Sheila K ;Booth, Scott A;Rana, Indrajeetsinh;Minoda, Yosuke;Berzins, Stuart P;Curl, Claire L;Bell, James R;Wai, Bryan;Srivastava, Piyush M ;Kangas, Antti J;Soininen, Pasi;Ruohonen, Saku;Kähönen, Mika;Lehtimäki, Terho;Raitoharju, Emma;Havulinna, Aki;Perola, Markus;Raitakari, Olli;Salomaa, Veikko;Ala-Korpela, Mika;Kettunen, Johannes;McGlynn, Maree;Kelly, Jason;Wlodek, Mary E;Lewandowski, Paul A;Delbridge, Lea M;Burrell, Louise M ;Inouye, Michael;Harrap, Stephen B;Charchar, Fadi J
Affiliation: School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia, Ballarat, Victoria, Australia
Medicine (University of Melbourne)
Heart Failure Research Group, Baker Heart and Diabetes Research Institute, Melbourne, Victoria, Australia
Centre for Systems Genomics, The University of Melbourne, Victoria, Australia
School of BioSciences, The University of Melbourne, Victoria, Australia
Department of Pathology, The University of Melbourne, Victoria, Australia
Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Victoria, Australia
Department of Physiology, The University of Melbourne, Victoria, Australia
NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Finland
Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland
Fimlab Laboratories, Department of Clinical Chemistry, Pirkanmaa Hospital District, School of Medicine, University of Tampere, Finland
National Institute for Health and Welfare, Helsinki, Finland
Institute for Molecular Medicine Finland, University of Helsinki, Finland
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
Medical Research Council Integrative Epidemiology Unit, University of Bristol, United Kingdom
School of Social and Community Medicine, University of Bristol, United Kingdom
School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
Department of Cardiovascular Sciences, University of Leicester, United Kingdom
Issue Date: 14-Jun-2017
Date: 2017
Publication information: Journal of the American Heart Association 2017; 6: e005971
Abstract: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction andLcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulatingLcn2was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure.Lcn2expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereasLcn2-knockout mice had smaller hearts. In cultured cardiomyocytes,Lcn2activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS,LCN2expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located nearLCN2defined a significantcis-eQTL forLCN2expression. Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.
DOI: 10.1161/JAHA.117.005971
ORCID: 0000-0003-1863-7539
Journal: Journal of the American Heart Association
PubMed URL: 28615213
Type: Journal Article
Subjects: C‐reactive protein
concentric hypertrophy
gene coexpression networks
systems biology
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