Role of the lipid peroxidation product, 4‐hydroxynonenal, in the in the development of nitrate tolerance

Abstract

Aldehyde dehydrogenase 2 (ALDH2) is important for the detoxification of 4‐hydroxy‐2‐nonenal (HNE), a toxic aldehyde produced by oxidative stress‐induced lipid peroxidation, which can form protein adducts and alter cell function. Tolerance to nitrates such as nitroglycerin (GTN) is associated with oxidative stress, inactivation of ALDH2, and decreased GTN‐induced cGMP accumulation and vasodilation. We hypothesized that GTN‐induced inactivation of ALDH2 results in increased HNE adduct formation of key proteins, and consequently an altered vasodilator response to GTN. This was assessed in a cell culture model (PK1 cells), and in aortae from GTN‐tolerant rats and ALDH2 null mice. Immunoblot analysis indicated a marked increase in HNE adduct formation in all three preparations. Preincubation of PK1 cells with HNE resulted in a dose‐dependent decrease in GTN‐induced cGMP accumulation, and pretreatment of isolated rat aorta with HNE resulted in dose‐dependent decreases in the vasodilator response to GTN, thus mimicking GTN‐tolerance. Pretreatment of aortae from ALDH2 null mice with 10 μM HNE also resulted in a desensitized vasodilator response, and mimicked the desensitized response observed in GTN tolerance. The data are consistent with the notion of a primary role of HNE protein adduct formation in the development of GTN tolerance. This work was supported by grant from the Canadian Institutes of Health Research (MOP 81175)