- Meeting abstract
- Open Access
Evaluating a possible role for PKG1α redox state in chronic hypoxia-induced pulmonary hypertension
© Rudyk et al. 2015
- Published: 2 September 2015
- Chronic Hypoxia
- Acute Hypoxia
- Hypoxic Pulmonary Vasoconstriction
- Pulmonary Vascular Remodelling
- Lung Hypoxia
Hypoxic pulmonary vasoconstriction is a physiological response enabling efficient oxygen delivery to tissues during transient regional lung hypoxia. However, when larger territories are involved, this adaptive mechanism can be detrimental and chronically lead to maladaptation. Such maladaptive events occur commonly due to high altitude hypoxia or pathologies that cause widespread, chronic pulmonary vasoconstriction resulting in hypoxic pulmonary arterial hypertension (HPAH), maladaptive pulmonary vascular remodelling and right heart failure. Previous work from our lab has shown protein kinase G (PKG) 1α is susceptible to oxidation, forming a disulfide dimer which directly activates the kinase resulting in vasodilation and blood pressure lowering. During hypoxia, pulmonary cells become pro-reducing. In this study we tested the hypothesis that this may alter the levels of oxidant-activated PKG1α and contribute to HPAH pathogenesis.
A “redox-dead” Cys42Ser PKGIα knock-in (KI) mouse which cannot be oxidant-activated was employed. HPAH was induced by exposing mice to 10% O2 for 4 weeks. Cardiac function and pulmonary arterial stiffness was assessed by echocardiography (VEVO 770, Visual Sonics). Right ventricular pressure was measured using a 1.2F pressure catheter (Scisence Inc). Vascular reactivity was assessed using a tension myograph (DMT). Tissues for molecular analysis were harvested under hypoxic (10% O2) or normoxic conditions (room air) respectively to reflect their treatment conditions.
We conclude that PKG1α plays a role in both acute hypoxic vasoconstriction as well as changes during chronic HPAH. We speculate that disulfide PKG1α levels are lowered, by chemical reduction, during acute hypoxia – potentially contributing to acute hypoxic pulmonary vasoconstriction. In contrast, during chronic hypoxia there is exacerbated PKG1α oxidation which may be protective by keeping the pulmonary arterial pressure low, and thereby reducing the afterload on the right ventricle in the setting of HPAH. Redox dead PKG1α KI mice lack this protective mechanism and therefore have exacerbated hypoxia-induced pulmonary hypertension phenotype. Interventions targeting PKG1α oxidation in the pulmonary vasculature will help to test if this mechanism truly serves to attenuate HPAH progression and consequent right heart failure.
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