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Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure.


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 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.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.

SUBMITTER: Marques FZ 

PROVIDER: S-EPMC5669193 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure.

Marques Francine Z FZ   Prestes Priscilla R PR   Byars Sean G SG   Ritchie Scott C SC   Würtz Peter P   Patel Sheila K SK   Booth Scott A SA   Rana Indrajeetsinh I   Minoda Yosuke Y   Berzins Stuart P SP   Curl Claire L CL   Bell James R JR   Wai Bryan B   Srivastava Piyush M PM   Kangas Antti J AJ   Soininen Pasi P   Ruohonen Saku S   Kähönen Mika M   Lehtimäki Terho T   Raitoharju Emma E   Havulinna Aki A   Perola Markus M   Raitakari Olli O   Salomaa Veikko V   Ala-Korpela Mika M   Kettunen Johannes J   McGlynn Maree M   Kelly Jason J   Wlodek Mary E ME   Lewandowski Paul A PA   Delbridge Lea M LM   Burrell Louise M LM   Inouye Michael M   Harrap Stephen B SB   Charchar Fadi J FJ  

Journal of the American Heart Association 20170614 6


<h4>Background</h4>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 expressi  ...[more]

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