p22phox C242T SNP inhibits inflammatory oxidative damage to endothelial cells and vessels

Meijles, D. N., Fan, L. M., Ghazaly, M. M., Howlin, B., Krönke, M., Brooks, G. and Li, J.-m. ORCID: https://orcid.org/0000-0002-3294-3818 (2016) p22phox C242T SNP inhibits inflammatory oxidative damage to endothelial cells and vessels. Circulation, 133 (24). pp. 2391-2403. ISSN 1524-4539 doi: 10.1161/CIRCULATIONAHA.116.021993

Abstract/Summary

Background— T NADPH oxidase, by generating reactive oxygen species, is involved in the pathophysiology of many cardiovascular diseases and represents a therapeutic target for the development of novel drugs. A single-nucleotide polymorphism (SNP) C242T of the p22phox subunit of NADPH oxidase has been reported to be negatively associated with coronary heart disease (CHD) and may predict disease prevalence. However, the underlying mechanisms remain unknown. Methods and Results— Using computer molecular modelling we discovered that C242T SNP causes significant structural changes in the extracellular loop of p22phox and reduces its interaction stability with Nox2 subunit. Gene transfection of human pulmonary microvascular endothelial cells showed that C242T p22phox reduced significantly Nox2 expression but had no significant effect on basal endothelial O2.- production or the expression of Nox1 and Nox4. When cells were stimulated with TNFα (or high glucose), C242T p22phox inhibited significantly TNFα-induced Nox2 maturation, O2.- production, MAPK and NFκB activation and inflammation (all p<0.05). These C242T effects were further confirmed using p22phox shRNA engineered HeLa cells and Nox2-/- coronary microvascular endothelial cells. Clinical significance was investigated using saphenous vein segments from non CHD subjects after phlebectomies. TT (C242T) allele was common (prevalence of ~22%) and compared to CC, veins bearing TT allele had significantly lower levels of Nox2 expression and O2.- generation in response to high glucose challenge. Conclusions— C242T SNP causes p22phox structural changes that inhibit endothelial Nox2 activation and oxidative response to TNFα or high glucose stimulation. C242T SNP may represent a natural protective mechanism against inflammatory cardiovascular diseases.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/65662
Item Type	Article
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Uncontrolled Keywords	genetics; endothelial dysfunction; NAD(P)H oxidase; oxidative stress; vessel
Publisher	American Heart Association
Download/View statistics	View download statistics for this item