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

• Published in: British journal of pharmacology 2008-02, Vol.153 (3), p.508-516
• Main Authors: Guns, P‐J, Assche, T, Verreth, W, Fransen, P, Mackness, B, Mackness, M, Holvoet, P, Bult, H
• Format: Article
• Language: English
• Subjects: Adenovirus; Animals; Aorta, Thoracic - pathology; apoE; Apolipoproteins E - genetics; Aryldialkylphosphatase - genetics; Aryldialkylphosphatase - pharmacology; atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - genetics; Atherosclerosis - therapy; Biological and medical sciences; Blood and lymphatic vessels; Calcium - metabolism; Cardiology. Vascular system; endothelial dysfunction; Endothelium, Vascular - metabolism; Gene Transfer Techniques; Homeostasis - genetics; Humans; Lipoproteins, LDL - blood; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; oxidative stress; Oxidative Stress - genetics; paraoxonase 1; Pharmacology. Drug treatments; Research Papers; Transfection - methods; vascular smooth muscle cells; Vasodilation - drug effects; Vasodilation - genetics
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707585

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−/−) mice with advanced atherosclerosis. Experimental approach: ApoE−/− mice (18 months, regular chow) were transfected with PON1 adenovirus (AdPON1, n=10) or control adenovirus (AdRR5, n=10). Non‐transfected apoE−/− (n=9) and C57Bl/6J (WT, n=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−/− 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−/− 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 Ca2+ homeostasis in segments with pre‐existing atherosclerosis, independently of an effect on plaque size. British Journal of Pharmacology (2008) 153, 508–516; doi:10.1038/sj.bjp.0707585; published online 3 December 2007