HIF-1α aggravates pathologic myopia through the miR-150-5p/LAMA4/p38 MAPK signaling axis

Abstract

Therapeutic inhibition of hypoxia-inducible factor-1alpha (HIF-1α) action has emerged as a potential approach for managing several diseases, including myopia. Herein, we analyzed the role of HIF-1α in the progression of pathologic myopia by regulating the miR-150-5p/LAMA4/p38 MAPK axis. Microarray-based gene expression profiling of pathologic myopia was employed to identify differentially expressed genes. Human scleral fibroblasts (HSFs) were cultured under the hypoxic conditions. Interaction among HIF-1α, miR-150-5p, and LAMA4 was identified. Gain- and loss-of-function experiments were performed in hypoxia-exposed HSFs to evaluate the effect of the HIF-1α/miR-150-5p/LAMA4/p38 MAPK axis on the extracellular matrix (ECM) degradation of HSFs and the subsequent pathologic myopia progression. Increased LAMA4 but decreased miR-150-5p was found in serum sample of pathologic myopia patients. HIF-1α and LAMA4 were abundantly expressed, and p38 MAPK was activated while miR-150-5p was weakly expressed in hypoxia-exposed HSFs. HIF-1α was enriched in the promoter region of miR-150-5p and downregulated its expression, thus repressing the ECM degradation of HSFs as shown by increased COL1A1 and TIMP-2 and reduced MMP2. In addition, LAMA4 was a downstream target of miR-150-5p and under the negative regulation by miR-150-5p. Overexpression of miR-150-5p promoted the ECM degradation of HSFs by inhibiting LAMA4 expression and p38 MAPK signaling pathway. However, upregulation of LAMA4 reversed the promoting effect of miR-150-5p on ECM degradation of HSFs. Overall, our findings suggest that HIF-1α can decline miR-150-5p expression and facilitate LAMA4-mediated p38 MAPK signaling pathway activation, thus arresting ECM degradation of HSFs and eventually inducing pathologic myopia.