FT011, a new anti‐fibrotic drug, attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy

Abstract

Aims Cardiac remodelling in diabetes includes pathological accumulation of extracellular matrix and myocyte hypertrophy that contribute to heart dysfunction. Attenuation of remodelling represents a potential therapeutic target. We tested this hypothesis using a new anti‐fibrotic drug, FT011 (Fibrotech Therapeutics Pty Ltd), on diabetic Ren‐2 rats, a model which replicates many of the structural and functional manifestations of diabetic cardiomyopathy in humans. Methods and results Homozygous Ren‐2 rats were randomized to receive streptozotocin or vehicle then further randomized to FT011 (200 mg/kg/day) or vehicle treatment for 6 weeks. Prior to tissue collection, cardiac function was assessed via echocardiography and cardiac catheterization. Total collagen deposition and cardiomyocyte hypertrophy were assessed by picrosirius red and haematoxylin and eosin staining, respectively. Macrophage interstitial infiltration and type I and III collagen were quantitated by immunostaining. Without affecting blood pressure or hyperglycaemia, treatment of diabetic rats with FT011 significantly attenuated interstitial fibrosis (total collagen, 5.09 ±1.28 vs, 2.42 ±0.43%/area; type I collagen, 4.09 ±1.16 vs. 1.42 ±0.38%/area; type III collagen, 1.52 ±0.33 vs. 0.71 ±0.14 %/area; P < 0.05), cardiomyocyte hypertrophy (882 ±38 vs. 659 ±28 µm2; P < 0.05), and interstitial macrophage influx (66 ±5.3 vs, 44 ±7.9 number/section; P < 0.05). Cardiac myopathic dilatation was normalized, as evidenced by reduced left ventricular inner diameter at diastole (0.642 ±0.016 vs. 0.577 ±0.024 cm), increased ejection fraction (75 ±1.1 vs. 83 ±1.2%) and preload recruitable stroke work relationship (44 ±6.7 vs. 77 ±6.3 slope‐mmHg; P < 0.05), and reduced end‐diastolic pressure–volume relationship (0.059 ±0.011 vs. 0.02 ±0.003 slope‐mmHg/μL; P < 0.05). Conclusions A direct anti‐fibrotic agent, FT011, attenuates cardiac remodelling and dysfunction in experimental diabetic cardiomyopathy. This represents a novel therapy for the treatment of diabetic cardiomyopathy associated with cardiac fibrosis and hypertrophy.

Cardiac Fibroblast-Dependent Extracellular Matrix Accumulation Is Associated with Diastolic Stiffness in Type 2 Diabetes

“…This data indicates that db/db hearts had decreased ventricular compliance. Diastolic dysfunction has been correlated with increased collagen deposition in multiple experimental models of diabetes [34], [35], and limiting pathological matrix accumulation attenuates cardiac remodeling improving ventricular function [36]. In this study, db/db hearts had increased collagen myocardial deposition with elevated collagen crosslinks as indicated by hydroxyproline content.…”

MMI-0100 inhibits cardiac fibrosis in myocardial infarction by direct actions on cardiomyocytes and fibroblasts via MK2 inhibition

“…However, clinical utility of these compounds is limited by multiple undesirable side effects, including liver toxicity [76]. Novel anti-fibrotic agents based on the core structure of Transilast (FT011) have subsequently been approved for pre-clinical development of diabetic nephropathy and have been tested for treatment of experimental diabetic cardiomyopathy [77, 78]. Use of relaxin to reduce fibrosis post-AMI has been reported [79] and use of recombinant relaxin in Phase 2 and Phase 3 clinical of acute heart failure and decompensated congestive heart failure have been completed, with results in process [80–82].…”

Novel targets of antifibrotic and anti-inflammatory treatment in CKD

“…6 Another oral analogue of tranilast, FT011, has been tested for antifibrotic effects in experimental models of kidney and heart fibrosis. 34 In two different rat models of CKD (5/6 nephrectomized rats and hypertensive Ren-2 transgenic rats with streptozotocin-induced diabetes), FT011 reduced protein uria, inflammation, and glomerulosclerosis. 35 FT011 also had a cardioprotective role in the diabetic Ren-2 rat model, attenuating cardiomyocyte hypertrophy as well as macrophage infiltration and interstitial fibrosis of heart tissue.…”

“…For example, the effects of FT011 might be mediated via inhibition of pathways involving Smad2 and mitogen-activated protein kinases 1 and 3. 34 Moreover, Smad3 has emerged as potentially the most important receptor-regulated phosphopeptide in the Smad family in relation to matrix accumulation: knock out of Smad3 protects against diabetic nephropathy, hypertensive kidney disease, and obstructive nephropathy. 37 Importantly, Smad3 is also phosphorylated via stimulation of angiotensin II, independent of TGF-β.…”