Paraoxonase 1 and atherosclerosis

Abstract

Paraoxonase 1 (PON1), residing almost exclusively on HDL, was discovered because of its hydrolytic activity towards organophosphates. Subsequently, it was also found to hydrolyse a wide range of substrates, including lactones and lipid hydroperoxides. PON1 is critical for the capacity of HDL to protect LDL and outer cell membranes against harmful oxidative modification, but this activity depends on its location within the hydrophobic lipid domains of HDL. It does not prevent conjugated diene formation, but directs lipid peroxidation products derived from these to become harmless carboxylic acids rather than aldehydes which might adduct to apolipoprotein B. Serum PON1 is inversely related to the incidence of new atherosclerotic cardiovascular disease (ASCVD) events, particularly in diabetes and established ASCVD. Its serum activity is frequently discordant with that of HDL cholesterol. PON1 activity is diminished in dyslipidaemia, diabetes, and inflammatory disease. Polymorphisms, most notably Q192R, can affect activity towards some substrates, but not towards phenyl acetate. Gene ablation or over-expression of human PON1 in rodent models is associated with increased and decreased atherosclerosis susceptibility respectively. PON1 antioxidant activity is enhanced by apolipoprotein AI and lecithin:cholesterol acyl transferase and diminished by apolipoprotein AII, serum amyloid A, and myeloperoxidase. PON1 loses this activity when separated from its lipid environment. Information about its structure has been obtained from water soluble mutants created by directed evolution. Such recombinant PON1 may, however, lose the capacity to hydrolyse non-polar substrates. Whilst nutrition and pre-existing lipid modifying drugs can influence PON1 activity there is a cogent need for more specific PON1-raising medication to be developed.

Keywords: PON1 polymorphism; cardiovascular disease; high density lipoprotein; lipid peroxidation; paraoxonase 1; paraoxonase 1 activity.

FIGURE 1

The accumulation of lipid peroxides on LDL and HDL when incubated alone and together in the presence of Cu²⁺. LDL + HDL significantly different from LDL alone. *P < 0.05; ^**P < 0.001.

FIGURE 2

The risk of ASCVD relative to the lowest risk quartile or quintile (RR) as a function of serum paraoxonase 1 (PON1) activity studied prospectively in (A) Caerphilly and Speedwell (CHD only) (65), (B) cleveland clinic (ASCVD and all-cause mortality) (72), and (C) meta-analysis by Kunutsor et al. (ASCVD) (70). Closed circles are RR unadjusted for other risk factors and open circles after adjustment for some of these (see references for details).

FIGURE 3

Symbolic representation of the peroxidation of phosphatidyl choline with linoleate in Sn2 by reactive oxygen species (hydroperoxy radical in this example). A superscript dot preceding an atom indicates an unpaired electron. (1) Hydrogen abstraction from the hydrocarbon chain leads to (2) rearrangement in which the double bonds between carbon 6 and 9 are no longer separated by 2 single bonds but by only one (conjugated diene formation). (3) Addition of oxygen then leads to peroxy radical formation with the potential for initiating a chain reaction and (4) spontaneous breakdown to aldehydes and ketones which can adduct to apolipoprotein B of LDL altering its receptor-binding. When PON1 in HDL is present breakdown to carboxylic acids rather than aldehydes and ketones is believed to occur.

FIGURE 4

Schematic representation of the mechanism by which HDL impedes the atherogenic modification of LDL. ApoA1, apolipoprotein AI; ApoAII, apolipoprotein AII; apoB, apolipoprotein B; ApoM, apolipoprotein M; PON1, paraoxonase 1; PLA2, phospholipase A2 (syn: PAFAH, platelet activating factor hydrolase); LCAT, lecithin cholesterol acyl transferase; SAA, serum amyloid A; PLTP, phospholipid transfer protein; CETP, cholesteryl ester transfer protein; SCARB1, scavenger receptor class B1; oxLDL, oxidatively modified LDL; LDLR, LDL receptor; L, lipid; ^●LOOH, hydroxylipid radical; ROS, reactive oxygen species (containing oxygen with an unpaired electron giving it an outer shell resembling fluorine).