Related Experiment Videos
Paraoxonase and coronary heart disease
M I Mackness1, B Mackness, P N Durrington
1University Department of Medicine, Manchester Royal Infirmary, UK.
Current Opinion in Lipidology
|September 18, 1998
Summary
Paraoxonase (PON1) enzyme activity, influenced by genetic variations, protects against oxidative stress. Lower PON1 levels are linked to coronary heart disease and diabetes, suggesting a role in atherosclerosis prevention.
Area of Science:
- Biochemistry
- Genetics
- Cardiovascular Science
Background:
- Paraoxonase (PON1) enzyme hydrolyzes organophosphate compounds, influencing mammalian toxicity.
- Human PON1 exhibits genetic polymorphisms at positions 55 and 192, affecting enzyme activity and substrate specificity.
- PON1's role in high-density lipoprotein (HDL) protection of low-density lipoprotein (LDL) against oxidative modification is crucial for cardiovascular health.
Purpose of the Study:
- To investigate the impact of PON1 genetic polymorphisms on enzyme activity and its implications for coronary heart disease (CHD).
- To explore the relationship between serum PON1 concentration, activity, and the development of CHD and diabetes.
- To determine PON1's role in preventing atherosclerosis by protecting lipoproteins from oxidative damage.
Main Methods:
- Analysis of human PON1 genetic polymorphisms at positions 55 and 192.
- Ex vivo studies assessing HDL's capacity to protect LDL against oxidative modification.
- Case-control studies examining serum PON1 levels and activity in patients with CHD and diabetes.
- Utilizing transgenic mice lacking PON1 to evaluate its protective function against LDL oxidation.
Main Results:
- The PON1 192 polymorphism significantly influences PON1 activity towards organophosphates, while the 55 polymorphism also modulates activity.
- PON1 polymorphisms are critical for HDL's ability to protect LDL from oxidative modification in vitro.
- Reduced serum PON1 concentration and activity were observed in CHD and diabetes, independent of PON1 genetic polymorphisms.
- HDL from PON1-deficient mice failed to protect LDL against oxidative modification.
Conclusions:
- PON1 genetic variations play a role in modulating enzyme activity and its protective functions.
- Decreased PON1 levels in serum are associated with cardiovascular disease and diabetes, irrespective of genetic background.
- PON1 is a key determinant in preventing atherosclerosis by protecting lipoproteins, potentially through hydrolyzing lipid hydroperoxides.