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C1q-TNF-Related Protein-9 Promotes Cardiac Hypertrophy and Failure
Mahesh Appari1, Astrid Breitbart1, Florian Brandes1
1From the Klinik für Kardiologie und Angiologie (M.A., A.B., F.B., M.S., N.F., M.K.-K., M.M.M., A.G., G.M.S., H.W., C.Z., D.F., U.S., K.C.W., J.B., J.H.) and Cluster of Excellence REBIRTH (M.A., A.B., F.B., M.S., N.F., M.K.-K., M.M.M., A.G., G.M.S., H.W., C.Z., U.S., K.C.W., J.B., J.H.), Medizinische Hochschule Hannover, Germany; Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Heilongjiang, China (H.W.); Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Canada (M.N.); Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, MD (G.W.W.); Department of Cardiology, University Hospital Heidelberg, Germany (H.A.K., O.J.M.); and DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany (H.A.K., O.J.M.).
Insights
Cardiac endothelial cells release CTRP9, a protein that worsens heart remodeling during pressure overload. Inhibiting CTRP9 or its downstream pathways may offer new therapeutic strategies for heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Endothelial Cell Biology
Background:
- Myocardial endothelial cells contribute to cardiomyocyte hypertrophy via growth factors.
- The specific endothelial-derived factors modulating heart remodeling are largely unknown.
- C1q-tumor necrosis factor-related protein-9 (CTRP9) is hypothesized to be an endothelial-derived protein involved in cardiac remodeling.
Purpose of the Study:
- To determine the source of cardiac CTRP9.
- To investigate the functional role of CTRP9 in cardiac remodeling during pressure overload.
Main Methods:
- Assessed CTRP9 expression in human and mouse hearts under pressure overload (transverse aortic constriction).
- Utilized CTRP9 gene-deleted (knock-out) and overexpressing mice models.
- Investigated downstream signaling pathways, including ERK5 and GATA4 activation.
- Employed in vitro and in vivo models to assess cardiac hypertrophy and dysfunction.
Main Results:
- CTRP9 is primarily derived from myocardial capillary endothelial cells and is upregulated in hypertrophic hearts.
- CTRP9 deficiency protected mice from pressure overload-induced cardiac hypertrophy and dysfunction.
- CTRP9 overexpression exacerbated cardiac remodeling and dysfunction.
- CTRP9 promotes hypertrophy via activation of the ERK5/GATA4 signaling pathway.
Conclusions:
- Upregulated CTRP9 in hypertrophic heart disease contributes to maladaptive cardiac remodeling and left ventricular dysfunction.
- CTRP9 represents a potential therapeutic target for treating heart disease.
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.
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