Paraoxonase 1 gene transfer lowers vascular oxidative stress and improves vasomotor function in apolipoprotein E‐deficient mice with pre‐existing atherosclerosis

Abstract

Background and purpose: Transgenesis of human paraoxonase 1 (PON1), a HDL-associated enzyme that destroys lipid peroxides, has been reported to reduce early atherogenesis in mice. The present study explored the therapeutic potential of human PON1 gene transfer in old apolipoprotein E-deficient (apoE À/À ) mice with advanced atherosclerosis. Experimental approach: ApoE À/À mice (18 months, regular chow) were transfected with PON1 adenovirus (AdPON1, n ¼ 10) or control adenovirus (AdRR5, n ¼ 10). Non-transfected apoE À/À (n ¼ 9) and C57Bl/6J (WT, n ¼ 6) mice served as controls. Three weeks later, plaque size and composition, and endothelial cell (EC) and smooth muscle cell (SMC) function were assessed in the aorta. Key results: PON1 gene transfer raised total PON1 serum activity 13-15 fold during the 3-week study period, without affecting hypercholesterolaemia or lesion size. However, PON1 decreased the oxLDL content of the plaque. Plaque-free thoracic aorta rings from apoE À/À mice displayed, like rings from WT mice, complete relaxation to acetylcholine (ACh, 86 ± 2%), ATP (90±2%) or UTP (83±3%). In contrast, in plaque-bearing segments amplitude (55±7%, 68±8%, 52±8% respectively) and sensitivity were decreased. EC function was completely (ATP, UTP) or largely (ACh) restored by AdPON1. Furthermore, apoE À/À SMCs released less intracellular calcium than WT upon sarco-endoplasmic reticulum calcium ATPase (SERCA) inhibition by cyclopiazonic acid. This defect was also restored by AdPON1 transfection. Conclusions and implications: These data indicate that AdPON1 gene transfer improved vascular wall oxidative stress, EC function, and SMC Ca 2 þ homeostasis in segments with pre-existing atherosclerosis, independently of an effect on plaque size.

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice

“…PON1, a member of the paraoxonase subfamily, is involved in the onset and development of cardiovascular diseases [35][36][37]. To explore whether PON1 participates in FGF21 protection against DCM, we first tested the expression of PON1 in both STZ/HFD-treated FGF21 KO and WT mice.…”

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

“…Finally, lesion formation was limited in our study by the time frame during which ApoE-KO mice developed intermediate or advanced atherosclerotic lesions. According to previous study, 35 adenovirus-mediated hPON1 gene transfer in ApoE-KO mice with preexisting atherosclerosis failed to reduce the plaque size, but did greatly improve oxidative stress and endothelial cell function in arteries.…”

Adenovirus-mediated human paraoxonase1 gene transfer to provide protection against the toxicity of the organophosphorus pesticide toxicant diazoxon

“…Studies addressing atherosclerosis through Ad-PON1 gene transfer were more successful, achieving 4-15-fold higher levels of PON1 in mice and improved vascular wall oxidative stress, endothelial cell function, smooth muscle cell Ca 2+ homeostasis and reduced oxidized LDL. 29,30 Purified rabbit and hPON1 Protection by PON1 from OP toxicity has been achieved by injecting purified rabbit PON1 into rats and mice. By increasing the PON activity 30-to 50-fold above endogenous levels, rats and mice were protected from the toxicity of chlorpyrifos oxon as measured by inhibition of AChE activity.…”