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Updated: May 11, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension
Oleksandra Prysyazhna1, Olena Rudyk, Philip Eaton
1King's College London, Cardiovascular Division, British Heart Foundation Centre of Excellence, Rayne Institute, St Thomas' Hospital, London, UK.
Insights
Hydrogen peroxide (H2O2) activates protein kinase G I-alpha (PKGI-α) for vasodilation. Blocking PKGI-α oxidation causes hypertension, highlighting its role in blood pressure regulation.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Hypertension Research
Background:
- Blood pressure regulation is vital for health; hypertension is a major risk factor for cardiovascular and renal diseases.
- Nitric oxide (NO) and prostacyclin are known vasodilators, but a significant vasorelaxation independent of these pathways, known as endothelium-derived hyperpolarizing factor (EDHF), exists.
- Hydrogen peroxide (H2O2) is a key component of EDHF, activating protein kinase G I-alpha (PKGI-α) via oxidation, leading to vasodilation.
Purpose of the Study:
- To investigate the in vivo role of PKGI-α oxidation in the EDHF mechanism.
- To determine the significance of PKGI-α oxidation in controlling blood pressure.
Main Methods:
- Generated a knock-in mouse model expressing a redox-dead mutant (C42S) of PKGI-α.
- Assessed the vasodilatory response to H2O2 in resistance blood vessels.
- Monitored blood pressure in the genetically modified mice.
Main Results:
- The C42S mutation in PKGI-α abolished the vasodilatory effect of H2O2 on resistance vessels.
- Mice expressing the redox-dead PKGI-α exhibited hypertension.
- This indicates that PKGI-α oxidation is essential for H2O2-mediated vasodilation and normal blood pressure.
Conclusions:
- PKGI-α oxidation is a critical pathway for EDHF-mediated vasodilation.
- This mechanism plays a significant role in the in vivo regulation of blood pressure.
- Targeting PKGI-α oxidation may offer therapeutic strategies for hypertension.
Abstract:
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. Hydrogen peroxide (H2O2) has been shown to be a major component of EDHF in several vascular beds in multiple species, including in humans. H2O2 causes the formation of a disulfide bond between the two α subunits of protein kinase G I-α (PKGI-α), which activates the kinase independently of the NO-cyclic guanosine monophosphate (cGMP) pathway and is coupled to vasodilation. To test the importance of PKGI-α 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-α. 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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