The Anti-Inflammatory Effect of the β1-Adrenergic Receptor Antagonist Metoprolol on High Glucose Treated Human Microvascular Retinal Endothelial Cells

Hyperglycemia-induced impairment of the blood-retinal barrier represents the main pathological event in diabetic retinopathy that is elicited by a reduced cellular response to an accumulation of reactive oxygen species (ROS) and increased inflammation. The purpose of the study was to evaluate whether the selective beta 1-adrenoreceptor (beta 1-AR) antagonist metoprolol could modulate the inflammatory response to hyperglycemic conditions. For this purpose, human retinal endothelial cells (HREC) were treated with normal (5 mM) or high glucose (25 mM, HG) in the presence of metoprolol (10 mu M), epinephrine (1 mu M), or both compounds. Metoprolol prevented both the HG-induced reduction of cell viability (MTT assays) and the modulation of the angiogenic potential of HREC (tube formation assays) reducing the TNF-alpha, IL-1 beta, and VEGF mRNA levels (qRT-PCR). Moreover, metoprolol prevented the increase in phospho-ERK1/2, phospho-cPLA(2), COX2, and protein levels (Western blot) as well as counteracting the translocation of ERK1/2 and cPLA(2) (high-content screening). Metoprolol reduced ROS accumulation in HG-stimulated HREC by activating the anti-oxidative cellular response mediated by the Keap1/Nrf2/HO-1 pathway. In conclusion, metoprolol exerted a dual effect on HG-stimulated HREC, decreasing the activation of the pro-inflammatory ERK1/2/cPLA(2)/COX2 axis, and counteracting ROS accumulation by activating the Keap1/Nrf2/HO-1 pathway.

Automated summary

This study evaluated the modulatory effect of the selective beta 1-adrenoreceptor antagonist metoprolol on the inflammatory response to hyperglycemic conditions. The results showed that metoprolol could reduce cell death and modulate the angiogenic potential, while decreasing the expression levels of inflammatory cytokines and angiogenesis-related genes. Furthermore, metoprolol inhibited the activation of the inflammatory signaling pathway and the accumulation of reactive oxygen species (ROS), while activating the anti-oxidative cellular response pathway.