The opposing effects of CCN2 and CCN5 on the development of cardiac hypertrophy and fibrosis.
CCN family members are matricellular proteins with diverse roles in cell function. The differential expression of CCN2 and CCN5 during cardiac remodeling suggests that these two members of the CCN family play opposing roles during the development of cardiac hypertrophy and fibrosis. We aimed to evaluate the role of CCN2 and CCN5 in the development of cardiac hypertrophy and fibrosis. In isolated cardiomyocytes, overexpression of CCN2 induced hypertrophic growth, whereas the overexpression of CCN5 inhibited both phenylephrine (PE)- and CCN2-induced hypertrophic responses. Deletion of the C-terminal (CT) domain of CCN2 transformed CCN2 into a CCN5-like dominant negative molecule. Fusion of the CT domain to the Carboxy-terminus of CCN5 transformed CCN5 into a CCN2-like pro-hypertrophic molecule. CCN2 transgenic (TG) mice did not develop cardiac hypertrophy at baseline but showed significantly increased fibrosis in response to pressure overload. In contrast, hypertrophy and fibrosis were both significantly inhibited in CCN5 TG mice. CCN2 TG mice showed an accelerated deterioration of cardiac function in response to pressure overload, whereas CCN5 TG mice showed conserved cardiac function. TGF-beta-SMAD signaling was elevated in CCN2 TG mice, but was inhibited in CCN5 TG mice. CCN2 is pro-hypertrophic and -fibrotic, whereas CCN5 is anti-hypertrophic and -fibrotic. CCN5 lacking the CT domain acts as a dominant negative molecule. CCN5 may provide a novel therapeutic target for the treatment of cardiac hypertrophy and heart failure.
Yoon
Pyoung Oh
PO
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, South Korea.
Lee
Min-Ah
MA
Cha
Hyeseon
H
Jeong
Moon Hee
MH
Kim
Jooyeon
J
Jang
Seung Pil
SP
Choi
Bo Youn
BY
Jeong
Dongtak
D
Yang
Dong Kwon
DK
Hajjar
Roger J
RJ
Park
Woo Jin
WJ
D000818:Animals; D006332:Cardiomegaly / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000737:chemistry / Q000378:metabolism*; D005355:Fibrosis; D006333:Heart Failure / Q000150:complications / Q000378:metabolism / Q000517:prevention & control; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010656:Phenylephrine; D011312:Pressure; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
C526318:CCN2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C539089:WISP-2 protein, mouse; D055513:Connective Tissue Growth Factor; D010656:Phenylephrine