TY - JOUR
T1 - FT23, an orally active antifibrotic compound, attenuates structural and functional abnormalities in an experimental model of diabetic cardiomyopathy
AU - Tan, Sih Min
AU - Zhang, Yuan
AU - Wang, Bing Hui
AU - Tan, Christina YR
AU - Zammit, Steven C
AU - Williams, Spencer John
AU - Krum, Henry
AU - Kelly, Darren James
PY - 2012
Y1 - 2012
N2 - 1. Diabetic cardiomyopathy is characterized by early diastolic
dysfunction and structural changes, such as interstitial
fibrosis and cardiac hypertrophy. Using the Ren-2 rat
model, we sought to investigate the effect of FT23 on the
structural and functional changes associated with diabetic
cardiomyopathy.
2. Heterozygous Ren-2 rats were rendered diabetic with
streptozotocin by tail vein injection. Rats were then treated
with FT23 (200 mg/kg per day by gavage twice daily) or vehicle
from Week 8 to Week 16 after the onset of diabetes.
Echocardiography was performed to assess heart function
before the rats were killed and their hearts collected for histological
and molecular biological assessment. The antifibrotic
effect of FT23 was compared with that of tranilast in neonatal
cardiac fibroblasts when stimulated with transforming
growth factor (TGF)-b (5 ng/mL) at 30, 50 and 100 umol/L.
3. FT23 exhibited greater inhibition of TGF-b-induced collagen
production in neonatal cardiac fibroblasts, as measured
by a [3H]-proline incorporation assay, compared with its
parental compound tranilast. In the in vivo study, FT23 significantly
attenuated the increased heart weight : bodyweight
ratio in FT23-treated diabetic Ren-2 rats. Diastolic dysfunction,
as measured by mitral valve (MV) E/A ratio and MV
deceleration time, was also significantly attenuated by FT23.
Picrosirius red-stained heart sections revealed that cardiac
fibrosis in the diabetic rats was reduced by FT23 compared
with that in vehicle-treated rats, with a concomitant reduction
in collagen I immunostaining and infiltration of macrophages,
as demonstrated by ED1 immunostaining.
4. The results of the present study suggest that FT23
inhibits the activity of TGF-b and attenuates structural and
functional manifestations of diastolic dysfunction observed in
a model of diabetic cardiomyopathy.
Key words: diabetic cardiomyopathy, diastolic dysfunction,
fibrosis, transforming growth factor-b.
AB - 1. Diabetic cardiomyopathy is characterized by early diastolic
dysfunction and structural changes, such as interstitial
fibrosis and cardiac hypertrophy. Using the Ren-2 rat
model, we sought to investigate the effect of FT23 on the
structural and functional changes associated with diabetic
cardiomyopathy.
2. Heterozygous Ren-2 rats were rendered diabetic with
streptozotocin by tail vein injection. Rats were then treated
with FT23 (200 mg/kg per day by gavage twice daily) or vehicle
from Week 8 to Week 16 after the onset of diabetes.
Echocardiography was performed to assess heart function
before the rats were killed and their hearts collected for histological
and molecular biological assessment. The antifibrotic
effect of FT23 was compared with that of tranilast in neonatal
cardiac fibroblasts when stimulated with transforming
growth factor (TGF)-b (5 ng/mL) at 30, 50 and 100 umol/L.
3. FT23 exhibited greater inhibition of TGF-b-induced collagen
production in neonatal cardiac fibroblasts, as measured
by a [3H]-proline incorporation assay, compared with its
parental compound tranilast. In the in vivo study, FT23 significantly
attenuated the increased heart weight : bodyweight
ratio in FT23-treated diabetic Ren-2 rats. Diastolic dysfunction,
as measured by mitral valve (MV) E/A ratio and MV
deceleration time, was also significantly attenuated by FT23.
Picrosirius red-stained heart sections revealed that cardiac
fibrosis in the diabetic rats was reduced by FT23 compared
with that in vehicle-treated rats, with a concomitant reduction
in collagen I immunostaining and infiltration of macrophages,
as demonstrated by ED1 immunostaining.
4. The results of the present study suggest that FT23
inhibits the activity of TGF-b and attenuates structural and
functional manifestations of diastolic dysfunction observed in
a model of diabetic cardiomyopathy.
Key words: diabetic cardiomyopathy, diastolic dysfunction,
fibrosis, transforming growth factor-b.
UR - http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1681.2012.05726.x/pdf
U2 - 10.1111/j.1440-1681.2012.05726.x
DO - 10.1111/j.1440-1681.2012.05726.x
M3 - Article
SN - 0305-1870
VL - 39
SP - 650
EP - 656
JO - Clinical and Experimental Pharmacology and Physiology
JF - Clinical and Experimental Pharmacology and Physiology
IS - 8
ER -