IL-6 has been shown to play a major role in
collagen up-regulation process during
cardiac hypertrophy, although the precise mechanism is still not known. In this study we have analyzed the mechanism by which
IL-6 modulates
cardiac hypertrophy. For the in vitro model, IL-6-treated cultured cardiac fibroblasts were used, whereas the in vivo
cardiac hypertrophy model was generated by renal artery
ligation in adult male Wistar rats (Rattus norvegicus). During induction of
hypertrophy, increased phosphorylation of STAT1, STAT3, MAPK, and ERK
proteins was observed both in vitro and in vivo. Treatment of fibroblasts with specific inhibitors for STAT1 (
fludarabine, 50 μM), STAT3 (S31-201, 10 μM),
p38 MAPK (
SB203580, 10 μM), and ERK1/2 (
U0126, 10 μM) resulted in down-regulation of IL-6-induced phosphorylation of specific
proteins; however, only S31-201 and
SB203580 inhibited
collagen biosynthesis. In ligated rats in vivo, only STAT3 inhibitors resulted in significant decrease in
collagen synthesis and
hypertrophy markers such as
atrial natriuretic factor and β-
myosin heavy chain. In addition, decreased heart weight to
body weight ratio and improved cardiac function as measured by echocardiography was evident in animals treated with STAT3 inhibitor or
siRNA. Compared with
IL-6 neutralization, more pronounced down-regulation of
collagen synthesis and regression of
hypertrophy was observed with STAT3 inhibition, suggesting that STAT3 is the major downstream signaling molecule and a potential therapeutic target for
cardiac hypertrophy.