Journal
NATURE MEDICINE
Volume 18, Issue 2, Pages 286-290Publisher
NATURE RESEARCH
DOI: 10.1038/nm.2603
Keywords
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Funding
- Medical Research Council
- British Heart Foundation
- Leducq Foundation
- UK Department of Health through the National Institute for Health Research comprehensive Biomedical Research Centre
- British Heart Foundation [PG/10/98/28655] Funding Source: researchfish
- Medical Research Council [G0700320, G1000458, G0600785] Funding Source: researchfish
- MRC [G0700320, G1000458, G0600785] Funding Source: UKRI
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Blood pressure regulation is crucial for the maintenance of health, and hypertension is a risk factor for myocardial infarction, heart failure, stroke and renal disease. Nitric oxide (NO) and prostacyclin trigger well-defined vasodilator pathways; however, substantial vasorelaxation in response to agents such as acetylcholine persists when the synthesis of these molecules is prevented. This remaining vasorelaxation activity, termed endothelium-derived hyperpolarizing factor (EDHF), is more prevalent in resistance than in conduit blood vessels and is considered a major mechanism for blood pressure control(1-4). Hydrogen peroxide (H2O2) has been shown to be a major component of EDHF in several vascular beds in multiple species, including in humans(5-10). H2O2 causes the formation of a disulfide bond between the two a subunits of protein kinase G I-alpha (PKGI-alpha), which activates the kinase independently of the NO-cyclic guanosine monophosphate (cGMP) pathway and is coupled to vasodilation(11). To test the importance of PKGI-alpha oxidation in the EDHF mechanism and blood pressure control in vivo, we generated a knock-in mouse expressing only a C42S 'redox-dead' version of PKGI-alpha. This amino acid substitution, a single-atom change (an oxygen atom replacing a sulfur atom), blocked the vasodilatory action of H2O2 on resistance vessels and resulted in hypertension in vivo.
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