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2015 ; 10
(4
): e0123257
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Endothelial-derived oxidative stress drives myofibroblastic activation and
calcification of the aortic valve
#MMPMID25874717
Farrar EJ
; Huntley GD
; Butcher J
PLoS One
2015[]; 10
(4
): e0123257
PMID25874717
show ga
AIMS: Oxidative stress is present in and contributes to calcification of the
aortic valve, but the driving factors behind the initiation of valve oxidative
stress are not well understood. We tested whether the valve endothelium acts as
an initiator and propagator of oxidative stress in aortic valve disease. METHODS
AND RESULTS: Calcified human aortic valves showed side-specific elevation of
superoxide in the endothelium, co-localized with high VCAM1 expression, linking
oxidative stress, inflammation, and valve degeneration. Treatment with
inflammatory cytokine TNF? increased superoxide and oxidative stress and
decreased eNOS and VE-cadherin acutely over 48 hours in aortic valve endothelial
cells (VEC) and chronically over 21 days in ex vivo AV leaflets. Co-treatment of
VEC with tetrahydrobiopterin (BH4) but not apocynin mitigated TNF?-driven VEC
oxidative stress. Co-treatment of ex vivo AV leaflets with TNF?+BH4 or
TNF?+peg-SOD rescued endothelial function and mitigated inflammatory responses.
Both BH4 and peg-SOD rescued valve leaflets from the pro-osteogenic effects of
TNF? treatment, but only peg-SOD was able to mitigate the fibrogenic effects,
including increased collagen and ?SMA expression. CONCLUSIONS: Aortic valve
endothelial cells are a novel source of oxidative stress in aortic valve disease.
TNF?-driven VEC oxidative stress causes loss of endothelial protective function,
chronic inflammation, and fibrogenic and osteogenic activation, mitigated
differentially by BH4 and peg-SOD. These mechanisms identify new targets for
tailored antioxidant therapy focused on mitigation of oxidative stress and
restoration of endothelial protection.
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