Upregulation of heme oxygenase-1 as an adaptive mechanism for protection against crotonaldehyde in human umbilical vein endothelial cells.

Crotonaldehyde, a highly reactive α, β-unsaturated aldehyde, is a ubiquitous environmental pollutant and a product of endogenous lipid peroxidation. It is also a major component of cigarette smoke and is present in many foods and beverages, and has also been linked to development of various diseases. Activation of endothelial cells by stimuli such as cigarette smoke is an important risk factor for cardiovascular diseases, including atherosclerosis. Heme oxygenase-1 (HO-1) is a protective antioxidant enzyme with a critical role in resistance to oxidative stress and other cellular functions. In this study, we examined the effects of crotonaldehyde on HO-1 induction and determined the signaling pathways in human umbilical vein endothelial cells (HUVECs). Inhibition of the protein kinase C-δ (PKC-δ) and p38 pathways resulted in significant blockage of crotonaldehyde-mediated HO-1 induction. Crotonaldehyde treatment caused a dramatic increase in translocation of NF-E2 related factor (Nrf2), leading to induction of HO-1. In addition, small interfering RNA knockdown of Nrf2 and treatment with the specific HO-1 inhibitor ZnPP exhibited an obvious increase of apoptosis of crotonaldehyde-treated HUVECs. Taken together, our results demonstrated that crotonaldehyde-induced HO-1 expression is mediated by the PKC-δ-p38 MAPK-Nrf2-HO-1 pathway in HUVECs, which is an adaptive response to oxidative stress.