Paraoxonase and atherosclerosis-related cardiovascular diseases

In humans, three paraoxonase (PON1, PON2, and PON3) genes are clustered on chromosome 7 at a locus that spans a distance around 170 kb. These genes are highly homologous to each other and have a similar protein structural organization. PON2 is the intracellular enzyme, which is expressed in many tissues and organs, while two other members of PON gene family are produced by liver and associate with high density lipoprotein (HDL). The lactonase activity is the ancestral. Besides lactones and organic phosphates, PONs can hydrolyze and therefore detoxify oxidized low density lipoprotein and homocysteine thiolactone, i.e. two cytotoxic compounds with a strong proatherogenic action. Indeed, PONs possess numerous atheroprotective properties, which include antioxidant activity, anti-inflammatory action, preserving HDL function, stimulation of cholesterol efflux, anti-apoptosis, anti-thrombosis, and anti-adhesion. PON genetic polymorphisms contribute to susceptibility/protection from atherosclerosis-related diseases. The bright antiatherogenic activity of the PON cluster makes it a promising target for the development of new therapeutic strategies.