Connective tissue growth factor overexpression in cardiomyocytes promotes cardiac hypertrophy and protection against pressure overload.

Abstract

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.

• Authors: Anna N Panek, Maximilian G Posch, Natalia Alenina, Santhosh K Ghadge, Bettina Erdmann, Elena Popova, Andreas Perrot, Christian Geier, Rainer Dietz, Rainer Dietz Ingo Morano, Ingo Morano, Michael Bader, Cemil Ozcelik
• Journal: PloS one (PLoS One) Vol. 4 Issue 8 Pg. e6743 (Aug 25 2009) ISSN: 1932-6203 [Electronic] United States
• PMID: 19707545 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Angiotensin II
• Connective Tissue Growth Factor
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase 4
• Isoproterenol
• Calcium

Topics

• Angiotensin II (administration & dosage)
• Animals
• Base Sequence
• Calcium (metabolism)
• Cardiomegaly (genetics, physiopathology, prevention & control)
• Connective Tissue Growth Factor (genetics, metabolism)
• DNA Primers
• Enzyme Activation
• Humans
• Isoproterenol (administration & dosage)
• MAP Kinase Kinase 4 (metabolism)
• Mice
• Mice, Transgenic
• Myocardial Ischemia (metabolism)
• Myocardium (cytology)
• Polymerase Chain Reaction
• Pressure
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats