The role of paraoxonase 1 activity in cardiovascular disease: potential for therapeutic intervention.
The antioxidant activity of high density lipoprotein (HDL) is largely due to the paraoxonase (PON) 1 located on it. Experiments with transgenic PON1 knockout mice indicate the potential for PON1 to protect against atherogenesis. This effect of HDL in decreasing low density lipoprotein (LDL) lipid peroxidation is maintained for longer than that of antioxidant vitamins and could therefore be more protective. Several important advances in the field of PON research have occurred recently, not least the discovery that two other members of the PON gene family -PON2 and PON3 - may also have important antioxidant properties. Significant advances have been made in understanding the basic biochemical function of PON1 and the discovery of possible modulators of its activity. Case-control studies of PON1 activity and coronary heart disease (CHD) have shown a clear association between CHD and low serum PON1 activity. This relationship has been further strengthened by the publication of the first prospective study showing low serum PON1 activity to be an independent predictor of new CHD events. Furthermore, decreased CHD risk has been revealed by meta-analysis to be associated with the polymorphisms of PON1, which are most active in lipid peroxide hydrolysis. Although this is likely to be an underestimate of the true contribution of PON1 to CHD (because these polymorphisms explain only a small component of the variation in PON1 activity), it is important because genetic influences are unlikely to be confounded by other factors linked with both CHD and diminished PON1 activity. PON1 is being extensively researched and it is hoped that therapeutic approaches will emerge to increase its activity. Clinical trials of these, if successful, will not only provide a novel means of preventing atherosclerosis, but also provide a more satisfactory means of testing the oxidant hypothesis of atherosclerosis than antioxidant vitamin supplementation has proved to be.
Mackness
Michael I
MI
University Department of Medicine, Manchester Royal Infirmary, Manchester, UK.
Durrington
Paul N
PN
Mackness
Bharti
B
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001161:Arteriosclerosis / Q000201:enzymology; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology*; D008076:Cholesterol, HDL / Q000378:metabolism; D006801:Humans; D009747:Nutritional Physiological Phenomena
D000975:Antioxidants; D008076:Cholesterol, HDL; D043303:Aryldialkylphosphatase