The term French paradox stands for the epidemiologically proven fact that the French suffer less from cardiovascular morbidity and mortality than other people with a comparable fat intake. This paradox was attributed to the rather high red wine consumption of the French. Several studies have stated a beneficial influence of purple grape products on oxidative stress. Since NADPH oxidases are one of the main contributors to vascular reactive oxygen species, we experimentally examined the effect of the purple grape products red wine and purple grape juice on Nox protein and activity in vitro and in vivo. The immunoreactivity of the vascular Nox isoforms Nox1, Nox2 and Nox4 in rat aortic tissue homogenates and of Nox4 in rat vascular smooth muscle cells (VSMC) following administration of red wine and / or purple grape juice was assessed. Nox activity was determined via measurement of superoxide production in VSMC and by performing isometric tension measurements on isolated rat thoracic aorta segments. The in vivo experiments were performed in healthy Wistar unilever rats (WUR) and in spontaneously hypertensive rats (SHR), which serve as a disease model for genetic hypertension. In vitro incubation with red wine and / or purple grape juice led dose-dependently to decreased Nox4 immunoreactive signals and to a lower superoxide production in VSMC. The apocynin inhibitable part of superoxide generation, a measure for Nox activity, was reduced by red wine only. However, oral treatment with both purple grape products did not significantly affect Nox protein levels in WUR. Surprisingly, ingestion of ethanol resulted in Nox4 overexpression, which was inhibited by red wine. Ex vivo endothelium-derived vasorelaxation in organbath chambers was not influenced by ingestion of purple grape products in WUR. Treating SHR with purple grape juice affected neither Nox protein expression nor vasofunction. The findings of this study strongly point out the discrepancy between in vitro and in vivo experiments in French paradox research. While direct application of purple grape products on VSMC had distinct effects on both Nox activity and protein expression, in vivo administration of the same liquids did not affect Nox protein expression and vasofunction. Thus, the origin of the French Paradox cannot be explained by NADPH oxidases. Since other experimental designs also were not able to conclusively identify possible pathways, the molecular mechanism of the French paradox is still unclear.
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