-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 p22(phox) 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.
-Using computer molecular modelling we discovered that C242T SNP causes significant structural changes in the extracellular loop of p22(phox) and reduces its interaction stability with Nox2 subunit. Gene transfection of human pulmonary microvascular endothelial cells showed that C242T p22(phox) 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 p22(phox) 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 p22(phox) 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.
-C242T SNP causes p22(phox) 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.
Pharmacology, Toxicology and Pharmaceutical Science
1
3%
Other
3
9%
Unknown
9
27%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 May 2019.
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#20,660,571
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