Nitrated fatty acids in cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of death and accounts for one third of disease-related mortality worldwide. Dysregulated redox mechanisms, in particular the formation of reactive oxygen species (ROS) play a pivotal pathogenetic role in CVD. Nitro-fatty acids (NO2-FAs) are electrophilic molecules which have a NO2-group bound to one of their olefinic carbons. They are endogenously formed by the reaction of reactive nitrogen species with unsaturated fatty acids. Basal levels of NO2-FAs are in the low nanomolar range and higher concentrations can be encountered under acidic (stomach) and inflammatory (e.g. ischemia/reperfusion) conditions. Dietary intake of polyunsaturated fatty acids in combination with nitrites raises circulating NO2-FAs to a clinically relevant level in mice. NO2-FAs undergo reversible covalent binding to cysteine residues and by virtue of these posttranslational protein modifications act as potent anti-inflammatory signaling mediators via modulation of various critical pathways like nuclear factor E2-related factor 2 (Nrf2)- and peroxisome proliferator-activated receptor γ (PPARγ) activation, nuclear factor-kappa B (NF-κB) inhibition and hem oxygenase-1 (HO-1)- and heat shock protein (HSP) induction. In this review article, we summarize recent findings about the effects and underlying molecular mechanisms of NO2-FAs from a variety of pre-clinical cardiovascular disease models. The described findings suggest the potential of NO2-FAs to emerge as therapeutic agents with a broad range of potential clinical applications for CVD.