Redox signalling by protein kinase G Iα in cardiovascular physiology and pathology

Abstract

Background Proteomic studies allowed us to identify PKA RIa and then PKG Ia as kinases that form interprotein disulfides in response to oxidants such as hydrogen peroxide (H2O2). This oxidation event directly activated PKG Ia independently of the classical NO-cGMP pathway to cause vasodilation. Subsequently we generated a Cys42Ser PKG Ia ‘redox-dead’ knock-in (KI) mouse. PKG Ia in these KI mice cannot be oxidant-activated as it lacks the thiol redox sensor. Consequently KI blood vessels do not relax fully to oxidants or endothelium derived hyperpolarising factor (EDHF) stimuli resulting in hypertension in vivo compared to wild-type (WT) littermates. This provided robust evidence PKG Ia oxidation is a significant mechanism of lowering BP in vivo. Additional studies showed cGMP binding to PKG induces a state that is resistant to disulfide formation. Thus interventions that lower cGMP stimulate PKG oxidation. Consequently, PKG oxidation occurs to a lesser extent in aortas than in mesenteries, as conduit vessels have higher levels of NO. Conduit vessels also express more peroxiredoxin and thioredoxin than resistance vessels, perhaps allowing oxidants such as H2O2 accumulate at higher levels in the latter. Together this helps explain why resistance vessels, principal regulators of blood pressure, are highly sensitive to PKG Ia oxidation and consequently oxidant-induced vasodilation compared to conduits.