title: FT23, an orally active antifibrotic compound, attenuates structural and functional abnormalities in an experimental model of diabetic cardiomyopathy.
abstract: 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. 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)-β (5 ng/mL) at 30, 50 and 100 umol/L. FT23 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, 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. The results of the present study suggest that FT23 inhibits the activity of TGF-β and attenuates structural and functional manifestations of diastolic dysfunction observed in a model of diabetic cardiomyopathy.
authors.affiliation: The University of Melbourne, Department of Medicine, St Vincent's Hospital, Fitzory, Australia.
authors.forename: Sih Min
authors.initials: SM
authors.lastname: Tan
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Christina Y R
authors.initials: CY
authors.lastname: Tan
authors.forename: Steven C
authors.initials: SC
authors.lastname: Zammit
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002109:Caffeic Acids / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D003094:Collagen / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004452:Echocardiography; D053331:Ectodysplasins / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis; D006579:Heterozygote; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D009205:Myocarditis / Q000209:etiology / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002109:Caffeic Acids; D003094:Collagen; D053331:Ectodysplasins; D005343:Fibrinolytic Agents; D062367:ortho-Aminobenzoates; C576530:2-((3-(3-(but-2-ynyloxy)-4-methoxyphenyl)-1-oxo-2-propenyl)amino)benzoic acid; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C506018:EDA protein, human