Abstract
OBJECTIVES:There is an urgent need to discover targets that can reverse established fibrosis that occurs with advanced ageing and in many disease states thus improving organ function. The aim of this study was to determine whether inhibition or deficiency of IRAP would reverse age-induced cardiac fibrosis and improve left ventricular function in 2 year old mice.
METHODS:Cardiovascular fibrosis and function (using echocardiography) was assessed in young (∼4–5 months old) and aged (∼22–24 months old) WT (C57BL/6J) or IRAP KO mice. Aged WT mice were chronically treated with either the synthetic IRAP inhibitor (HFI-419; 500 ng/kg/min) or vehicle for 4 or 8 weeks.
RESULTS:Ageing resulted in marked interstitial cardiac fibrosis and increased IRAP expression that was co-localised with myofibroblasts. Global IRAP gene deletion protected against age-induced fibrosis and resulted in improved left ventricular function. Importantly chronic treatment with 3 structurally-unrelated specific IRAP inhibitors for 4 weeks reversed established cardiac fibrosis in aged mice. Mechanisms involved down-regulation of collagen synthesis, increased collagen degradation and reduced tissue inflammation. In separate animals, we examined if HFI-419 treatment for 8 weeks improved left ventricular function assessed by serial echocardiography at weeks 0, 4 and 8. Our preliminary data suggest improvement of left ventricular function within 4 weeks of HFI-419 treatment and was associated with reduced cardiac fibrosis in these mice.
CONCLUSION:Our data provides compelling evidence that inhibition of IRAP represents a novel therapeutic strategy for treatment of established cardiac fibrosis leading to improved organ function.