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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Am+Coll+Cardiol
2016 ; 67
(13
): 1556-1568
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Matricellular Protein CCN5 Reverses Established Cardiac Fibrosis
#MMPMID27150688
Jeong D
; Lee MA
; Li Y
; Yang DK
; Kho C
; Oh JG
; Hong G
; Lee A
; Song MH
; LaRocca TJ
; Chen J
; Liang L
; Mitsuyama S
; D'Escamard V
; Kovacic JC
; Kwak TH
; Hajjar RJ
; Park WJ
J Am Coll Cardiol
2016[Apr]; 67
(13
): 1556-1568
PMID27150688
show ga
BACKGROUND: Cardiac fibrosis (CF) is associated with increased ventricular
stiffness and diastolic dysfunction and is an independent predictor of long-term
clinical outcomes of patients with heart failure (HF). We previously showed that
the matricellular CCN5 protein is cardioprotective via its ability to inhibit CF
and preserve cardiac contractility. OBJECTIVES: This study examined the role of
CCN5 in human heart failure and tested whether CCN5 can reverse established CF in
an experimental model of HF induced by pressure overload. METHODS: Human hearts
were obtained from patients with end-stage heart failure. Extensive CF was
induced by applying transverse aortic constriction for 8 weeks, which was
followed by adeno-associated virus-mediated transfer of CCN5 to the heart. Eight
weeks following gene transfer, cellular and molecular effects were examined.
RESULTS: Expression of CCN5 was significantly decreased in failing hearts from
patients with end-stage heart failure compared to nonfailing hearts. Trichrome
staining and myofibroblast content measurements revealed that the established CF
had been reversed by CCN5 gene transfer. Anti-CF effects of CCN5 were associated
with inhibition of the transforming growth factor beta signaling pathway. CCN5
significantly inhibited endothelial-mesenchymal transition
and fibroblast-to-myofibroblast transdifferentiation, which are 2 critical
processes for CF progression, both in vivo and in vitro. In addition, CCN5
induced apoptosis in myofibroblasts, but not in cardiomyocytes or fibroblasts,
both in vivo and in vitro. CCN5 provoked the intrinsic apoptotic pathway
specifically in myofibroblasts, which may have been due the ability of CCN5 to
inhibit the activity of NF?B, an antiapoptotic molecule. CONCLUSIONS: CCN5 can
reverse established CF by inhibiting the generation of and enhancing apoptosis of
myofibroblasts in the myocardium. CCN5 may provide a novel platform for the
development of targeted anti-CF therapies.
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