Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25104350
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Deficiency of cardiomyocyte-specific microRNA-378 contributes to the development
of cardiac fibrosis involving a transforming growth factor ? (TGF?1)-dependent
paracrine mechanism
#MMPMID25104350
Nagalingam RS
; Sundaresan NR
; Noor M
; Gupta MP
; Solaro RJ
; Gupta M
J Biol Chem
2014[Sep]; 289
(39
): 27199-27215
PMID25104350
show ga
Understanding the regulation of cardiac fibrosis is critical for controlling
adverse cardiac remodeling during heart failure. Previously we identified miR-378
as a cardiomyocyte-abundant miRNA down-regulated in several experimental models
of cardiac hypertrophy and in patients with heart failure. To understand the
consequence of miR-378 down-regulation during cardiac remodeling, our current
study employed a locked nucleic acid-modified antimiR to target miR-378 in vivo.
Results showed development of cardiomyocyte hypertrophy and fibrosis in mouse
hearts. Mechanistically, miR-378 depletion was found to induce TGF?1 expression
in mouse hearts and in cultured cardiomyocytes. Among various secreted cytokines
in the conditioned-media of miR-378-depleted cardiomyocytes, only TGF?1 levels
were found to be increased. The increase was prevented by miR-378 expression.
Treatment of cardiac fibroblasts with the conditioned media of miR-378-depleted
myocytes activated pSMAD2/3 and induced fibrotic gene expression. This effect was
counteracted by including a TGF?1-neutralizing antibody in the
conditioned-medium. In cardiomyocytes, adenoviruses expressing dominant negative
N-Ras or c-Jun prevented antimiR-mediated induction of TGF?1 mRNA, documenting
the importance of Ras and AP-1 signaling in this response. Our study demonstrates
that reduction of miR-378 during pathological conditions contributes to cardiac
remodeling by promoting paracrine release of profibrotic cytokine, TGF?1 from
cardiomyocytes. Our data imply that the presence in cardiomyocyte of miR-378
plays a critical role in the protection of neighboring fibroblasts from
activation by pro-fibrotic stimuli.
free
free
free
