FT23, an orally active antifibrotic compound, attenuates structural and functional abnormalities in an experimental model of diabetic cardiomyopathy

Sih Min Tan, Yuan Zhang, Bing Hui Wang, Christina YR Tan, Steven C Zammit, Spencer John Williams, Henry Krum, Darren James Kelly

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10 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)650 - 656
Number of pages7
JournalClinical and Experimental Pharmacology and Physiology
Volume39
Issue number8
DOIs
Publication statusPublished - 2012

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