Role of miR-132 in Angiogenesis after Ocular Infection with Herpes Simplex Virus

Abstract

MicroRNAs (miRNAs) are small regulatory molecules that control diverse biological processes that include angiogenesis. Herpes simplex virus (HSV) causes a chronic immuno-inflammatory response in the eye that may result in corneal neovascularization during blinding immunopathological lesion stromal keratitis (SK). miR-132 is a highly conserved miRNA that is induced in endothelial cells in response to growth factors, such as vascular endothelial growth factor (VEGF). In this study, we show that miR-132 expression was up-regulated (10- to 20-fold) after ocular infection with HSV, an event that involved the production of both VEGF-A and IL-17. Consequently, blockade of VEGF-A activity using soluble VEGF receptor 1 resulted in significantly lower levels of corneal miR-132 after HSV infection. In addition, low levels of corneal miR-132 were detected in IL-17 receptor knockout mice after HSV infection. In vivo silencing of miR-132 by the provision of anti-miR-132 (antagomir-132) nanoparticles to HSV-infected mice led to reduced corneal neovascularization and diminished SK lesions. The anti-angiogenic effect of antagomir-132 was reflected by a reduction in angiogenic Ras activity in corneal CD31-enriched cells (presumably blood vessel endothelial cells) during SK. To our knowledge, this is one of the first reports of miRNA involvement in an infectious ocular disease. Manipulating miRNA expression holds promise as a therapeutic approach to control an ocular lesion that is an important cause of human blindness.

MicroRNA-132 targets PEA-15 and suppresses the progression of astrocytoma in vitro

“…As a member of the miRNAs family, miR-132 plays an important role in inflammation, angiogenesis, and neural development [12][13][14]. Recent studies show that the dysregulation of miR-132 is related to a variety of human tumors, such as non-small cell lung cancer (NSCLC), osteosarcoma, breast cancer, hepatocellular carcinoma, prostate cancer, gastric cancer, and pancreatic cancer [15][16][17][18][19][20][21].…”

MicroRNA-215 Regulates Fibroblast Function: Insights from a Human Fibrotic Disease

“…Due to accessibility of the lesion, there is greater potential for findings to be translated to medicine using local injection of microRNA intervention, limiting issues of systemic toxicity. 44 MicroRNAs have been implicated in the development of fibrosis via extracellular matrix and proliferative changes especially in liver, kidney and lung fibrotic diseases. 5,45,46 In this study, we aimed to ascertain the role of microRNAs in fibroblast function, using human pterygium as a model.…”

Potential Function of miRNAs in Herpetic Stromal Keratitis

“…How miR-132 promotes angiogenesis during HSK simultaneously by degrading angiogenic MMP-9 needs further investigation. 12,43 However, miR-132 blockadeinduced reduction in CV and expression of miR-132 in blood vessel endothelial cells while MMP-9 in neutrophils make MMP-9 an unlikely target of miR-132 during HSK.…”

“…34 We have also shown that miR-132 is also upregulated in animals with CV following HSV infection. 12 In the HSV system, the upregulation of miR-132 may be in part the consequence of stimulation by an as-yetunidentified mechanism by IL-17, a cytokine produced early in HSK pathogenesis by gamma delta cells of the innate immune system. 35 The upregulated miR-132 appears to act to augment VEGF signaling via an inhibitory effect on a negative regulator of VEGF function, Ras-GAP.…”

“…As we discuss, the CV process is subject to control by one or more species of miRNAs, with a recent publication implicating the relevance of miR-132. 12 …”