Isothiocyanates protect against oxidized LDL-induced endothelial dysfunction by upregulating Nrf2-dependent antioxidation and suppressing NFκB activation

Abstract

Scope: Oxidative stress plays a pivotal role in the pathophysiology of cardiovascular diseases. Oxidized low-density lipoprotein (oxLDL) is a key contributor to atherogenesis through multiple mechanisms. In this study, we investigated the protection by three structurally related isothiocyanates, i.e., sulforaphane (SFN), benzyl isothiocyanate (BITC), and phenethyl isocyanate (PEITC), against oxLDL-induced leukocyte adhesion to vascular endothelium and the mechanism involved.

Methods and results: The protection against oxLDL-induced endothelial dysfunction by isothiocyanates was studied in human umbilical vein endothelial cells (HUVECs). oxLDL increased reactive oxygen species (ROS) production, stimulated nuclear factor-kappaB (NFκB) activation, and enhanced intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin expression in HUVECs, which led to promotion of monocyte adhesion to HUVECs. Treatment with SFN, BITC, and PEITC (0-10 μM) dose-dependently induced heme oxygenase (HO)-1, glutamate cysteine ligase (GCL) catalytic and modifier subunit expression, intracellular glutathione content, and antioxidant response element (ARE)-luciferase reporter activity. SFN, BITC, and PEITC pretreatment reversed oxLDL-induced ROS production, NFκB nuclear translocation, κB-reporter activity, ICAM-1, VCAM-1, and E-selectin expression, and monocyte adhesion to endothelial cells. Both heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) knockdown attenuated the isothiocyanate inhibition of oxLDL-induced ROS production, κB-reporter activity, and adhesion molecule expression.

Conclusion: SFN, BITC, and PEITC protect against oxLDL-induced endothelial damage by upregulating Nrf2-dependent HO-1 and GCL expression, which leads to inhibition of NFκB activation and ICAM-1, VCAM-1, and E-selectin expression.

Keywords: Adhesion molecules; Glutamate cysteine ligase; Heme oxygenase 1; Isothiocyanates; Nuclear factor erythroid 2-related factor 2 (Nrf2); Nuclear factor-kappaB (NFκB); Oxidized LDL.