Abstract

People with diabetes have a five-fold higher incidence of cardiovascular disease, the leading cause of death globally. FKBPL is a novel angiogenesis-related protein, with a critical role in physiological and pathological angiogenesis. A first-in-class clinical FKBPL peptide mimetic, ALM201, has successfully completed clinical trials for treatment of solid tumours. FKBPL haploinsufficient (Fkbpl^± ) mice, have a pro-angiogenic phenotype, accompanied by vascular dysfunction. Vascular dysfunction is associated with CVD and T2D.

In view of these findings, we now investigate a specific role for FKBPL in angiogenesis associated with cardiac dysfunction. In streptozotocin (STZ)-induced diabetic mice (50 mg/kg i.p. for 5 consecutive days), cardiac FKBPL mRNA levels were downregulated at 12 weeks compared to vehicle controls (p<0.05, n=5); this was associated with diastolic dysfunction (e.g. mitral valve E/A ratio). Similarly, in an experimental mouse model of myocardial infarction (MI) associated with severe cardiac ischaemia/hypoxia and increased angiogenesis, FKBPL mRNA (p<0.05) and protein levels (p<0.01) were downregulated versus sham controls (n≥3). Complementary in vitro studies using human umbilical vein endothelial cells (HUVEC) demonstrated increased migration and differentiation following 24 hour exposure to hypoxia (1%) when compared to normoxia (p<0.01, n=6). In addition, FKBPL protein levels were downregulated following exposure to hypoxia (p<0.01, n=6), whilst activation of HIF-1α in normoxia by 24 hour DMOG treatment led to a two-fold reduction in FKBPL protein levels (p<0.01, n=3). Furthermore, HUVEC exposed to high glucose (30 mM for 24 hour) demonstrated downregulation of FKBPL compared to osmotic control (p<0.05, n=3). Interestingly, fenofibrate (50 µM) treatment was able to restore HUVEC levels of FKBPL in hypoxia (p<0.01, n=3). In conclusion, FKBPL may serve a key regulatory role in pathological angiogenesis associated with cardiac dysfunction and, as such, could be promising as a novel biomarker and therapeutic target in this disease setting.