C1q-TNF-Related Protein-9 Promotes Cardiac Hypertrophy and Failure

RATIONALE:Myocardial endothelial cells promote cardiomyocyte hypertrophy, possibly through the release of growth factors. The identity of these factors, however, remains largely unknown, and we hypothesized here that the secreted CTRP9 (C1q-tumor necrosis factor–related protein-9) might act as endot...

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Published in:Circulation research 2017-01, Vol.120 (1), p.66-77
Main Authors: Appari, Mahesh, Breitbart, Astrid, Brandes, Florian, Szaroszyk, Malgorzata, Froese, Natali, Korf-Klingebiel, Mortimer, Mohammadi, Mona Malek, Grund, Andrea, Scharf, Gesine M, Wang, Honghui, Zwadlo, Carolin, Fraccarollo, Daniela, Schrameck, Ulrike, Nemer, Mona, Wong, G William, Katus, Hugo A, Wollert, Kai C, Müller, Oliver J, Bauersachs, Johann, Heineke, Joerg
Format: Article
Language:English
Subjects:
Adiponectin - biosynthesis
Animals
Aortic stenosis
Cardiomegaly - metabolism
Cardiomegaly - pathology
Cardiomyocytes
Cells, Cultured
Coronary artery disease
Endothelial cells
Extracellular signal-regulated kinase
Gene expression
Glycoproteins - biosynthesis
Growth factors
Heart diseases
Heart Failure - metabolism
Heart Failure - pathology
Humans
Hypertrophy
Kinases
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation
Pressure
Proteins
Rats
Rats, Sprague-Dawley
Stenosis
Tumor necrosis factor
Tumor necrosis factor-TNF
Ventricle
Ventricular Dysfunction, Left - metabolism
Ventricular Dysfunction, Left - pathology
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Summary:RATIONALE:Myocardial endothelial cells promote cardiomyocyte hypertrophy, possibly through the release of growth factors. The identity of these factors, however, remains largely unknown, and we hypothesized here that the secreted CTRP9 (C1q-tumor necrosis factor–related protein-9) might act as endothelial-derived protein to modulate heart remodeling in response to pressure overload. OBJECTIVE:To examine the source of cardiac CTRP9 and its function during pressure overload. METHODS AND RESULTS:CTRP9 was mainly derived from myocardial capillary endothelial cells. CTRP9 mRNA expression was enhanced in hypertrophic human hearts and in mouse hearts after transverse aortic constriction (TAC). CTRP9 protein was more abundant in the serum of patients with severe aortic stenosis and in murine hearts after TAC. Interestingly, heterozygous and especially homozygous knock-out C1qtnf9 (CTRP9) gene-deleted mice were protected from the development of cardiac hypertrophy, left ventricular dilatation, and dysfunction during TAC. CTRP9 overexpression, in turn, promoted hypertrophic cardiac remodeling and dysfunction after TAC in mice and induced hypertrophy in isolated adult cardiomyocytes. Mechanistically, CTRP9 knock-out mice showed strongly reduced levels of activated prohypertrophic ERK5 (extracellular signal-regulated kinase 5) during TAC compared with wild-type mice, while CTRP9 overexpression entailed increased ERK5 activation in response to pressure overload. Inhibition of ERK5 by a dominant negative MEK5 mutant or by the ERK5/MEK5 inhibitor BIX02189 blunted CTRP9 triggered hypertrophy in isolated adult cardiomyocytes in vitro and attenuated mouse cardiomyocyte hypertrophy and cardiac dysfunction in vivo, respectively. Downstream of ERK5, we identified the prohypertrophic transcription factor GATA4, which was directly activated through ERK5-dependent phosphorylation. CONCLUSIONS:The upregulation of CTRP9 during hypertrophic heart disease facilitates maladaptive cardiac remodeling and left ventricular dysfunction and might constitute a therapeutic target in the future.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.116.309398