Pan-EphB tyrosine kinase inhibitor mitigates diabetic cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is characterized by myocardial fibrosis, excessive collagen deposition, decline in ejection fraction and diastolic dysfunction in diabetic subjects. As current pharmaceuticals have varying efficacy and adverse effects, there is an unmet need for new therapeutics. We recently identified STA-013, a pan-EphB tyrosine kinase inhibitor sparing EphB3, that resulted in whole-body weight loss, restored glucose homeostasis, and mitigated insulin resistance in diet-induced obese mouse models. Here, we now show in a streptozotocin (STZ)-high-fat diet-induced mouse model that STA-013 decreased body weight and restored glucose homeostasis while mitigating insulin resistance. Importantly, STA-013 significantly improved cardiac function in part by increasing ejection fraction and fractional shortening, and reduced collagen deposition suggestive of decreased cardiac fibrosis. This was associated with a significant downregulation of key molecular intermediaries including phosphorylation EphB tyrosine kinase signaling, insulin receptor signal, and TGF-{beta} levels in STA-013 treated STZ-HFD mice. Together, our preclinical findings support the development of pan-EphB tyrosine kinase inhibitors as novel therapeutics to mitigate DCM and associated complications.