Fodipir and Its Dephosphorylated Derivative Dipyridoxyl Ethyldiamine Are Involved in Mangafodipir-Mediated Cytoprotection against 7β-Hydroxycholesterol-Induced Cell Death

Abstract

Objective: Mangafodipir exerts pharmacological effects, including vascular relaxation and protection against oxidative stress and cell death induced by oxysterols. Additionally, mangafodipir has been proposed for cardiovascular imaging. The primary metabolites of mangafodipir, manganese dipyridoxyl ethyldiamine (MnPLED) and its constituent dipyridoxyl diphosphate (Dp-dp) also known as fodipir, are pharmacologically active. However, whether they affect oxysterol-induced cytotoxicity is currently unknown. In this study, we examine whether the mangafodipir metabolite affects 7β-hydroxycholesterol (7β-OH)-induced cell death and identify the underlying mechanisms. Methods: U937 cells were pretreated or not with mangafodipir substrate (Ms; 200 µm), MnPLED (100 µmol/l) or Dp-dp (100 µmol/l) for 8 h and then exposed to 7β-OH (28 µmol/l) for 18 h. Results: Our results revealed that pretreatment with MnPLED or Dp-dp protected against 7β-OH-induced cellular reactive oxygen species (ROS) production, apoptosis, and lysosomal membrane permeabilization (LMP). MnPLED and Dp-dp, in par with Ms, confer protection against 7β-OH-induced cytotoxicity by reducing cellular ROS and stabilization of the lysosomal membrane. Conclusion: These results suggest that fodipir is the pharmacologically active part in the structure of mangafodipir, which prevents 7β-OH-induced cell death by attenuating cellular ROS and by preventing LMP. In addition, MnPLED, which is the dephosphorylated product of fodipir, exerts a similar protective effect against 7β-OH-induced cytotoxicity. This result indicates that dephosphorylation of fodipir does not affect its pharmacological actions. Altogether our result confirms the cytoprotective effect of mangafodipir and justifies its potential use as a cytoprotective adjuvant.

27-Hydroxycholesterol Contributes to Lysosomal Membrane Permeabilization-Mediated Pyroptosis in Co-cultured SH-SY5Y Cells and C6 Cells

“…The effects of oxysteroids on structure and function of lysosomes have been proposed in a previous study (Boya, 2012). Excessive accumulation of oxysteroids in cells can lead to leakage of lysosomal membrane (Laskar et al, 2013; Yuan et al, 2016). However, as one of the important oxidation products of cholesterol, how 27-OHC influences the structure and function of lysosomes remains unknown.…”

“…Cholesterol oxidation metabolites have been found to be one of the important factors inducing LMP (Boya, 2012). Cell experiments in vitro found that 7β-hydroxycholesterol (7β-OHC)and 7-ketocholesterol (7-KC) can induce cell death through LMP (Laskar et al, 2013; Yuan et al, 2016). However, whether 27-OHC, as one of the important oxysterols, can lead to LMP is still unclear.…”