Uncoupling Protein 2 (UCP2): Another Player in the Complex Drama of Vascular Salt Sensitivity

Long-term follow-up studies in humans have shown that salt-sensitive individuals are not only more prone to develop hypertension than salt-resistant people, but also have a higher mortality rate, even if they do not develop hypertension.1 Short-term increases in dietary salt intake lead to increased vascular oxidant stress and dramatic reductions in endothelium-dependent dilation in rats without an increase in arterial pressure.2 The latter finding may provide valuable clues toward understanding salt-induced cardiovascular disease in light of the compelling review by Widlansky et al.3 stressing that endothelial dysfunction is a powerful predictor of adverse cardiovascular events, including death, in humans. The study by Ma and coworkers4 shows that, compared to wild-type (WT) C57Bl/6J controls, long-term (24 weeks) exposure to high-salt (HS) diet (8% NaCl) leads to an elevated blood pressure and more severe vascular dysfunction (increased norepinephrine contraction and impaired dilation to acetylcholine) in knockout mice genetically deficient in uncoupling protein 2 (UCP2), which dissipates the proton gradient that contributes to superoxide formation in the mitochondria. In contrast, HS diet does not increase blood pressure in WT mice; and the alterations in vascular reactivity, the salt-induced elevation in vascular superoxide levels and the reduction in NO availability, although still present, are less severe in WT mice than in the UCP−/− mice. These changes reflect an integrated whole body response to elevated dietary salt intake, because increases in extracellular Na+ alone do not mimic the effects of HS diet in cultured vascular smooth muscle cells from WT and UCP2−/− mice.4 Taken together, these findings suggest a potential link between mitochondrial sources of reactive oxygen species and the vascular dysfunction that occurs with long-term exposure to HS diet. The authors conclude that UCP2 has a compensatory role to offset the hypertensive effects of the HS diet, and to partially offset salt-induced vascular dysfunction.