血管收縮素誘發心臟纖維化之分子機制:Thiazolidinedione之抑制作用

Fibroblasts play an important role in
maintaining cardiac function by providing
structural support for the cardiomyocytes and
serving as a source for autocrine/paracrine
growth factors. After myocardial infarction,
reactive fibrosis results in excessive scar
formation as proliferating fibroblasts invade the
necrotic area. This remodeling leads to an
increase of the ventricular stiffness and
ultimately compromises the function of the
heart. Recent studies in humans and animal
models have shown that the expression of
myocardial endothelin-1 (ET-1) is increased
during cardiac fibrosis. It is suggested that ET-1
might contribute to cardiac fibroblast
proliferation resulting in cardiac fibrosis. ET-1
works as a paracrine as well as an autocrine. In
the first part of this project, our data revealed
that angiotensin II (Ang II)-stimulated
fibroblast proliferation is mediated by release
of ET-1 from fibroblasts rather than by direct
action.
Rosiglitazone, approved by the FDA
during the spring of 1999, was the second
thiazolidinedione to be marketed in the United
States. Rosiglitazone improves insulin
sensitivity in patients with type 2 diabetes by
activating peroxisome proliferator-activated
receptor-γ (PPAR摯瑬敳獩 ) receptors in adipose tissues,
skeletal muscles, and the liver. Using Northern
blot analysis and reverse
transcriptase-polymerase chain reaction in
samples of rat heart, Wayman et al. (2002)
documented the expression of the mRNA for
PPAR摯瑬敳獩 (isoform 1 but not isoform 2) in freshly
isolated cardiac myocytes and cardiac
fibroblasts and in the left and right ventricles of
the heart. Using a rat model of regional
myocardial ischemia and reperfusion (in vivo),
Wayman et al. (2002) discovered that
rosiglitazone causes a substantial reduction of
myocardial infarct size in the rat. Treatment of
normal and diabetic rat hearts with
rosiglitazone, also improves postischemic
functional recovery. Using Western
immunoblotting, it was demonstrated that the
acute cardioprotective effect of rosiglitazone is
associated with an inhibition of Jun
NH(2)-terminal kinase phosphorylation in both
normal and diabetic rat hearts. Furthermore,
rosiglitazone also inhibited activating
protein-1(AP-1) DNA-binding activity.
Our data indicate that rosiglitazone
inhibits Ang II–induced proliferation in cardiac
fibroblasts. Ang II increased DNA synthesis
which was inhibited with rosiglitazone.
Rosiglitazone inhibited the Ang II-induced
ET-1 gene expression as revealed by Nothern
blotting and promoter activity assay.
Rosiglitazone also inhibited Ang II-increased
intracellular ROS generation as measured by a
redox sensitive fluorescent dye, 2'
7'-dichlorofluorescin diacetate, and ERK
phosphorylation. Furthermore, rosiglitazone
and antioxidants such as N-acetyl-cysteine and
diphenylene iodonium decreased Ang
II-induced cell proliferation, ET-1 promoter
activity, ET-1 mRNA, ERK phosphorylation,
and activator protein-1-mediated reporter
activity. In summary, our results suggest that
rosiglitazone inhibits Ang II-induced cell
proliferation and ET-1 gene expression,
partially by interfering with the ERK pathway
via attenuation of ROS generation.