Salubrinal attenuated retinal neovascularization by inhibiting CHOP-HIF1α-VEGF pathways

Abstract

Retinal neovascularization (RNV) related disease is the leading cause of irreversible blindness in the world. The aim of this study is to identify whether salubrinal could attenuate RNV by inhibiting CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP)- hypoxia inducible factors 1α (HIF1α) -vascular endothelial growth factor (VEGF) pathways in both mouse retinal microvascular endothelial cells (mRMECs) and oxygen-induced retinopathy (OIR) mouse model. After being treated with salubrinal (20μmol/L) or CHOP-siRNA, mRMECs were exposed to a hypoxia environment. OIR mice were intraperitoneally injected with salubrinal (0.5 mg/kg/day) from P12 to P17. With salubrinal or CHOP-siRNA treatment, the elevated CHOP protein and mRNA levels in hypoxia-induced mRMECs were significantly decreased. HIF1α-VEGF pathways were activated under hypoxia condition, then HIF1α protein was degraded and VEGF secretion was down-regulated after salubrinal or CHOP-siRNA treatment. In OIR mice, the areas of RNV were markedly decreased with salubrinal treatment. Moreover, elevated expressions of CHOP, HIF1α and VEGF in retinas of OIR mice were all reduced after salubrinal treatment. It suggested that salubrinal attenuated RNV in mRMECs and OIR mice by inhibiting CHOP-HIF1α-VEGF pathways and could be a potential therapeutic target for hypoxia-induced retinal microangiopathy.

Epigenetic silencing of microRNA‐874‐3p implicates in erectile dysfunction in diabetic rats by activating the Nupr1/Chop‐mediated pathway

“…47 More specifically, Chop has been shown to be related to vascular disorders. 48,49 Therefore, it is possible that Nupr1/Chop-mediated endoplasmic reticulum stress-related pathway is involved in DMED, and merits further in-depth investigations. Knockdown of Nupr1 can trigger an augmented expression of antioxidant, making it a potential key factor in skin reactive oxygen species (ROS) responses.…”

“…Chop is a transcription factor that mediates endoplasmic reticulum stress‐induced apoptosis . More specifically, Chop has been shown to be related to vascular disorders . Therefore, it is possible that Nupr1/Chop‐mediated endoplasmic reticulum stress‐related pathway is involved in DMED, and merits further in‐depth investigations.…”

Arterial instillation of rapamycin in treatment of rabbit hepatic xenograft tumors and its effects on VEGF, iNOS, HIF-1α, Bcl-2, Bax expression and microvessel density

“…VEGF is an early vascular permeability factor and a vascular endothelial cell-specific heparin-binding growth factor that stimulates the division and proliferation of vascular endothelial cells and induces neovascularization in vivo; 15 VEGF is currently the most powerful protein factor that promotes angiogenesis and plays a key role in the formation of tumor blood vessels and the proliferation of tumors. 16 The expression of iNOS in tissues is related to the proliferation and growth of tumors.…”

Inhibition of CD146 attenuates retinal neovascularization via vascular endothelial growth factor receptor 2 signalling pathway in proliferative diabetic retinopathy

“…Exclusion criteria included previous PPV, co-existent other ocular angiogenesis disease or inflammatory disease. The OIR model was induced as described by Smith et al (1994) and our previous studies (Hu et al 2017;Xu et al 2018). Newborn C57BL/6J mice and their mother were exposed to 75% oxygen from postnatal day 7 (P7) to P12 and then returned to normal environment, while the control group was persistently kept in normal environment.…”