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FT 23, an orally active antifibrotic compound, attenuates structural and functional abnormalities in an experimental model of diabetic cardiomyopathy
Author(s) -
Tan Sih Min,
Zhang Yuan,
Wang Bing,
Tan Christina YR,
Zammit Steven C,
Williams Spencer J,
Krum Henry,
Kelly Darren J
Publication year - 2012
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2012.05726.x
Subject(s) - diabetic cardiomyopathy , medicine , endocrinology , immunostaining , fibrosis , cardiac fibrosis , streptozotocin , cardiomyopathy , cardiac function curve , diabetes mellitus , heart failure , immunohistochemistry
Summary Diabetic cardiomyopathy is characterized by early diastolic dysfunction and structural changes, such as interstitial fibrosis and cardiac hypertrophy. Using the R en‐2 rat model, we sought to investigate the effect of FT 23 on the structural and functional changes associated with diabetic cardiomyopathy. Heterozygous R en‐2 rats were rendered diabetic with streptozotocin by tail vein injection. Rats were then treated with FT 23 (200 mg/kg per day by gavage twice daily) or vehicle from W eek 8 to W eek 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 FT 23 was compared with that of tranilast in neonatal cardiac fibroblasts when stimulated with transforming growth factor ( TGF )‐β (5 ng/mL) at 30, 50 and 100 umol/L. FT 23 exhibited greater inhibition of TGF ‐β‐induced collagen production in neonatal cardiac fibroblasts, as measured by a [ 3 H ]‐proline incorporation assay, compared with its parental compound tranilast. In the in vivo study, FT 23 significantly attenuated the increased heart weight : bodyweight ratio in FT 23‐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 FT 23. Picrosirius red‐stained heart sections revealed that cardiac fibrosis in the diabetic rats was reduced by FT 23 compared with that in vehicle‐treated rats, with a concomitant reduction in collagen I immunostaining and infiltration of macrophages, as demonstrated by ED 1 immunostaining. The results of the present study suggest that FT 23 inhibits the activity of TGF ‐β and attenuates structural and functional manifestations of diastolic dysfunction observed in a model of diabetic cardiomyopathy.