Studies on protective effects of human paraoxonases 1 and 3 on atherosclerosis in apolipoprotein E knockout mice

Abstract

Paraoxonase (PON) possesses antiatherogenic potentials, but the distinct functions of PON members in alleviating atherosclerosis are not yet clear. This study aimed to evaluate the protective effects of hPON1 and hPON3 against atherosclerosis, and thereby exploring their synergistic mechanism in atherosclerosis development. We generated the recombinant adenovirus AdPON1 and AdPON3, which were capable of expressing hPON1 and hPON3. After AdPON1 and AdPON3 were injected intravenously into 5-week-old apolipoprotein E knockout mice, abundant hPON1 and hPON3 mRNA expression levels were detected. However, increase in serum lactonase activity was detected only in AdPON1-treated mice. Serum antioxidation and antiinflammation capabilities in AdPON1-treated mice, reflected by malondialdehyde, total antioxidant capability and tumor necrosis factor-a levels, were greatly enhanced, whereas those in AdPON3-treated mice were not significantly affected. Nevertheless, histological analysis revealed that adenovirus-mediated expression of hPON1, hPON3 or both of them reduced atherosclerotic plaque area to a similar extent. Although no synergistic mechanism was detected in reducing arterial lesion size, hPON1 and hPON3 showed synergistic effects on promoting macrophage cholesterol efflux. In conclusion, hPON1 and hPON3 exhibited similar potentials in reducing arterial lesion size, but they exerted antiatherogenic effects in distinct ways.

Immunohistochemical analysis of paraoxonases-1 and 3 in human atheromatous plaques

“…On the other hand, the overexpression of human PON3 in mouse models of atherosclerosis results in no HDL-associated PON3 in mouse circulation, but human PON3 was expressed in several mouse tissues [17,22]. Expression of PON3 significantly reduced atherosclerosis; however, all the effects appeared to be Reasons for these differences are unclear; however, differences in gene expression between monocytes isolated from blood and those infiltrating the aortic wall cannot be ruled out.…”

“…However, a recent study in apo-E-deficient mice showed that the injection of human recombinant PON3 decreased plaque size without changes in lipid peroxidation levels [22].…”

Impairment of High-Density Lipoprotein Resistance to Lipid Peroxidation and Adipose Tissue Inflammation in Obesity Complicated by Obstructive Sleep Apnea

“…Adenovirus based overexpression of human PON1 in apolipoprotein E knock-out mice is associated with reduced TNF␣ levels (43). Serum PON1 activity is correlated to serum TNF␣ levels in atheromatous patients with RA (44) and TNF␣ antagonist therapy leads to enhanced PON1 levels, heightened antioxidant capacity of HDL and a reduced inflammatory status (11).…”

Dysfunctional HDL and atherosclerotic cardiovascular disease

“…PON1 and PON3 differ in their expression profile, protein localization, and enzymatic activity, but are considered to have similar effects on the hydrolysis of oxidized lipids and promotion of macrophage cholesterol efflux in experimental models 70 . Although low levels of PON1 activity were associated with a modest inverse risk of CHD in a population-based study, this relationship was abolished after adjustment for HDL-C and apoA-I, suggesting that low PON1 activity is not a causal factor in atherogenesis 71 .…”