TY - JOUR
T1 - C1q-TNF-Related Protein-9 Promotes Cardiac Hypertrophy and Failure
AU - Appari, Mahesh
AU - Breitbart, Astrid
AU - Brandes, Florian
AU - Szaroszyk, Malgorzata
AU - Froese, Natali
AU - Korf-Klingebiel, Mortimer
AU - Mohammadi, Mona Malek
AU - Grund, Andrea
AU - Scharf, Gesine M.
AU - Wang, Honghui
AU - Zwadlo, Carolin
AU - Fraccarollo, Daniela
AU - Schrameck, Ulrike
AU - Nemer, Mona
AU - Wong, G. William
AU - Katus, Hugo A.
AU - Wollert, Kai C.
AU - Müller, Oliver J.
AU - Bauersachs, Johann
AU - Heineke, Joerg
N1 - Funding Information:
Sources of Funding This study was supported by the Deutsche Forschungsgemeinschaft through the Cluster of Excellence Rebirth (EXC 62/1 to K.C. Wollert, J. Bauersachs, and J. Heineke), the Heisenberg Program (HE 3658/6- 1 and HE 3658/6-2 to J. Heineke) and additional research grants (HE3658/8-1 to J. Heineke and MU1654/9-1 to O.J. Müller).
Publisher Copyright:
© 2016 American Heart Association, Inc.
PY - 2017/1/6
Y1 - 2017/1/6
N2 - 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.
AB - 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.
KW - aortic valve stenosis
KW - endothelial cells
KW - hypertrophy
KW - phosphorylation
KW - signal transduction
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U2 - 10.1161/CIRCRESAHA.116.309398
DO - 10.1161/CIRCRESAHA.116.309398
M3 - Article
C2 - 27821723
AN - SCOPUS:84995519521
SN - 0009-7330
VL - 120
SP - 66
EP - 77
JO - Circulation research
JF - Circulation research
IS - 1
ER -