Decreased Atherosclerotic Lesion Formation in Human Serum Paraoxonase Transgenic Mice

Abstract

Background-Serum paraoxonase (PON1), an enzyme carried on HDL, inhibits LDL oxidation, and in human population studies, low PON1 activity is associated with atherosclerosis. In addition, PON1 knockout mice are more susceptible to lipoprotein oxidation and atherosclerosis. To evaluate whether PON1 protects against atherosclerosis and lipid oxidation in a dose-dependent manner, we generated and studied human PON1 transgenic mice. Methods and Results-Human PON1 transgenic mice were produced by using bacterial artificial chromosome genomic clones. The mice had 2-to 4-fold increased plasma PON1 levels, but plasma cholesterol levels were unchanged. Atherosclerotic lesions were significantly reduced in the transgenic mice when both dietary and apoE-null mouse models were used. HDL isolated from the transgenic mice also protected against LDL oxidation more effectively. Conclusions-Our results indicate that PON1 protects against atherosclerosis in a dose-dependent manner and suggest that it may be a potential target for developing therapeutic agents for the treatment of cardiovascular disease.

HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress

“…Studies of animal models [5][6][7] and in humans [8,9] are consistent with the hypothesis that PON1 decreases the risk of cardiovascular disease by lowering levels of oxidative stress, notably lipoprotein oxidation. In earlier studies, we proposed that HDL acquires PON1 by desorption from the hepatic cell membrane in a process probably mediated or facilitated by transient anchoring of HDL to the membrane [10].…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…In fact, HDL from mice lacking PON1 were unable to prevent the accumulation of lipid peroxides in LDL and these mice demonstrated an increased susceptibility to atherosclerosis, 144 while introduction of the human PON1 transgene in mice had opposite effects on the anti-oxidative functions of HDL and atherosclerosis. 145 Interestingly, if residing on the same HDL particle, PON1 and MPO were found to interact and reciprocally affect each other's enzymatic activity. 146 PON1 inhibited MPO peroxidase activity, whereas in parallel site-specific oxidative modification of PON1 by MPO impaired PON1 function.…”

Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

“…PON1 has protective action against atherosclerosis in both in vitro and in vivo models. Indeed, PON1 protects LDL particles against copper-induced lipid oxidation in vitro [3,28,29] and transgenic mice overexpressing the human PON1 gene have reduced atherosclerotic lesions [48]. Moreover, PON1 knockout mice display accelerated atherosclerosis progression and increased lipid oxidation [40,42,43].…”