Journal
HYPERTENSION
Volume 64, Issue 6, Pages 1344-1351Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.114.04281
Keywords
blood pressure; hydrogen sulfide; oxidation-reduction; PKGI alpha; vasodilation
Categories
Funding
- European Research Council (ERC)
- Medical Research Council
- British Heart Foundation
- Fondation Leducq
- Department of Health via National Institute for Health Research comprehensive Biomedical Research Centre
- MRC [MR/L009684/1, G1000458, MR/K003232/1, G0700320, G0600785] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/C503646/1] Funding Source: researchfish
- British Heart Foundation [RG/12/12/29872, FS/14/1/30551, FS/11/45/28859, PG/10/98/28655] Funding Source: researchfish
- Medical Research Council [MR/L009684/1, G0700320, G0600785, G1000458, MR/K003232/1] Funding Source: researchfish
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Dysregulated blood pressure control leading to hypertension is prevalent and is a risk factor for several common diseases. Fully understanding blood pressure regulation offers the possibility of developing rationale therapies to alleviate hypertension and associated disease risks. Although hydrogen sulfide (H2S) is a well-established endogenous vasodilator, the molecular basis of its blood-pressure lowering action is incompletely understood. H2S-dependent vasodilation and blood pressure lowering in vivo was mediated by it catalyzing formation of an activating interprotein disulfide within protein kinase G (PKG) I alpha. However, this oxidative activation of PKG I alpha is counterintuitive because H2S is a thiol-reducing molecule that breaks disulfides, and so it is not generally anticipated to induce their formation. This apparent paradox was explained by H2S in the presence of molecular oxygen or hydrogen peroxide rapidly converting to polysulfides, which have oxidant properties that in turn activate PKG by inducing the disulfide. These observations are relevant in vivo because transgenic knockin mice in which the cysteine 42 redox sensor within PKG has been systemically replaced with a redox-dead serine residue are resistant to H2S-induced blood pressure lowering. Thus, a primary mechanism by which the reductant molecule H2S lowers blood pressure is mediated somewhat paradoxically by the oxidative activation of PKG.
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