The activity of
glucose-6-phosphate dehydrogenase (G6PD) controls a vascular smooth muscle relaxing mechanism promoted by the oxidation of cytosolic
NADPH, which has been associated with activation of the 1α form of
protein kinase G (PKG-1α) by a
thiol oxidation-elicited subunit dimerization. This PKG-1α-activation mechanism appears to contribute to responses of isolated endothelium-removed bovine pulmonary arteries (BPA) elicited by
peroxide, cytosolic
NADPH oxidation resulting from G6PD inhibition, and
hypoxia.
Dehydroepiandrosterone (
DHEA) is a
steroid hormone with pulmonary
vasodilator activity, which has beneficial effects in treating
pulmonary hypertension. Because multiple mechanisms have been suggested for the vascular effects of
DHEA and one of the known actions of
DHEA is inhibiting G6PD, we investigated whether it promoted relaxation associated with
NADPH oxidation, PKG-1α dimerization, and PKG activation detected by increased
vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Relaxation of BPA to
DHEA under aerobic or hypoxic conditions was associated with
NADPH oxidation, PKG-1α dimerization, and increased VASP phosphorylation. The
vasodilator activity of
DHEA was markedly attenuated in pulmonary arteries and aorta from a PKG knockin mouse containing a
serine in place of a
cysteine involved in PKG dimerization.
DHEA promoted increased PKG dimerization in lungs from wild-type mice, which was not detected in the PKG knockin mouse model. Thus PKG-1α dimerization is a major contributing factor to the
vasodilator actions of
DHEA and perhaps its beneficial effects in treating
pulmonary hypertension.