A novel prohibitin inhibitor acts as a dual inhibitor of angiogenesis and fibrosis.

Abstract

We previously showed that the benzoylphenylurea derivative BPU17 inhibits epithelial-mesenchymal transition and acts as an antifibrotic agent. This compound acts as a prohibitin (PHB) inhibitor by directly binding to PHB1. This binding disrupts the interaction between PHB1 and PHB2, leading to mild mitochondrial dysfunction. Here, we investigated the effect of BPU17 on angiogenesis using primary cultures of human vascular and microvascular endothelial cells, as well as a mouse model of choroidal neovascularization (CNV). A series of studies has shown that BPU17 inhibits angiogenesis both in vitro and in vivo. The molecular mechanism is that BPU17 inhibits serum response factor (SRF)/CArG box-mediated transcription by repressing the expression of SRF and its cofactor myocardin-related transcription factors (MRTF-A and -B [MRTF]). This defect causes the downregulation of adaptor and cell adhesion molecules such as vinculin and integrins, leading to the inhibition of angiogenesis. This inhibitory effect is closely associated with mild mitochondrial dysfunction, and siRNA-mediated knockdown of PHB1 similarly inhibits angiogenesis. Given that age-related inflammatory responses and subsequent choroidal neovascularization (CNV) contribute to the development of neovascular age-related macular degeneration (nAMD), this novel PHB inhibitor holds promise as a treatment for nAMD through its dual inhibitory effects on angiogenesis and fibrosis.