Connective tissue growth factor overexpression in cardiomyocytes promotes cardiac hypertrophy and protection against pressure overload.
Connective tissue growth factor (CTGF) is a secreted protein that is strongly induced in human and experimental heart failure. CTGF is said to be profibrotic; however, the precise function of CTGF is unclear. We generated transgenic mice and rats with cardiomyocyte-specific CTGF overexpression (CTGF-TG). To investigate CTGF as a fibrosis inducer, we performed morphological and gene expression analyses of CTGF-TG mice and rat hearts under basal conditions and after stimulation with angiotensin II (Ang II) or isoproterenol, respectively. Surprisingly, cardiac tissues of both models did not show increased fibrosis or enhanced gene expression of fibrotic markers. In contrast to controls, Ang II treated CTGF-TG mice displayed preserved cardiac function. However, CTGF-TG mice developed age-dependent cardiac dysfunction at the age of 7 months. CTGF related heart failure was associated with Akt and JNK activation, but not with the induction of natriuretic peptides. Furthermore, cardiomyocytes from CTGF-TG mice showed unaffected cellular contractility and an increased Ca(2+) reuptake from sarcoplasmatic reticulum. In an ischemia/reperfusion model CTGF-TG hearts did not differ from controls.Our data suggest that CTGF itself does not induce cardiac fibrosis. Moreover, it is involved in hypertrophy induction and cellular remodeling depending on the cardiac stress stimulus. Our new transgenic animals are valuable models for reconsideration of CTGF's profibrotic function in the heart.
Panek
Anna N
AN
Department of Cardiovascular and Metabolic Disease Research, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Posch
Maximilian G
MG
Alenina
Natalia
N
Ghadge
Santhosh K
SK
Erdmann
Bettina
B
Popova
Elena
E
Perrot
Andreas
A
Geier
Christian
C
Dietz
Rainer
R
Morano
Rainer Dietz Ingo
RD
Morano
Ingo
I
Bader
Michael
M
Ozcelik
Cemil
C
D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D007545:Isoproterenol / Q000008:administration & dosage; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D016133:Polymerase Chain Reaction; D011312:Pressure; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats
D017931:DNA Primers; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4; D007545:Isoproterenol; D002118:Calcium
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