Paraoxonase and cardiovascular disease: actions and interactions.
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RU Radboud Universiteit Nijmegen, 29 juni 2006
Promotor : Stalenhoef, A.F.H. Co-promotores : Tits, L.J.H. van, Roest, M., Voorbij, H.A.
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SubjectNCEBP 14: Cardiovascular diseases; UMCN 2.2: Vascular medicine and diabetes
Paraoxonase type 1 (PON1) is an enzyme which belongs to the family of paraoxonases. Other members of the paraoxonase family are PON2 and PON3. In the human body, PON1 is located exclusively on the high-density lipoprotein (HDL) particle. As the name 'paraoxonase' indicates, PON1 can hydrolyze the highly toxic organophosphate and insecticide 'paraoxon'. Since paraoxon is a toxic chemical compound, it is not plausible that the hydrolysis of paraoxon is the primary biological function of PON1. Many research groups have previously suggested that the prevention of oxidation of low-density lipoprotein (LDL), is an important beneficial function of PON1 in the human body. Because the oxidation of LDL is one of the first steps in the development of atherosclerosis, the inhibition of LDL oxidation by PON1 may be an important step in the prevention of cardiovascular disease (CVD). There are also indications that PON1 can prevent the oxidation of the HDL particle and as a result preserve the beneficial function of HDL in the reverse cholesterol transport, i.e. the cholesterol efflux from macrophages. Since cholesterol efflux is an important function of the HDL particle, this interaction may also be an important second function of PON1. In this thesis, we have addressed the following questions regarding PON1. 1.) To what extent does PON1 inhibit the oxidation of LDL? 2.) Does PON1 influence the functioning of the HDL particle and as a result the lipid metabolism? 3.) To what extent does PON1 contribute to the onset of CVD. The main outcome of our studies is that, in contrast to what has been frequently suggested by other investigators, we cannot confirm that PON1 plays an important role in the oxidation of LDL in the human body. We do find that PON1 may have other effects which relate to CVD. We find that higher PON1 levels contribute to higher HDL-cholesterol levels in the body, demonstrating a beneficial role for PON1 in the lipid metabolism
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