A1 Refereed original research article in a scientific journal
Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure
Authors: Marques FZ, Prestes PR, Byars SG, Ritchie SC, Wurtz P, Patel SK, Booth SA, Rana I, Minoda Y, Berzins SP, Curl CL, Bell JR, Wai B, Srivastava PM, Kangas AJ, Soininen P, Ruohonen S, Kahonen M, Lehtimaki T, Raitoharju E, Havulinna A, Perola M, Raitakari O, Salomaa V, Ala-Korpela M, Kettunen J, McGlynn M, Kelly J, Wlodek ME, Lewandowski PA, Delbridge LM, Burrell LM, Inouye M, Harrap SB, Charchar FJ, Harrap SB, Charchar FJ
Publisher: WILEY
Publication year: 2017
Journal: Journal of the American Heart Association
Journal name in source: JOURNAL OF THE AMERICAN HEART ASSOCIATION
Journal acronym: J AM HEART ASSOC
Article number: ARTN e005971
Volume: 6
Issue: 6
Number of pages: 57
ISSN: 2047-9980
DOI: https://doi.org/10.1161/JAHA.117.005971
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/25706856
Background-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.Methods and Results-We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-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 circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated 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, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression.Conclusions-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.
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