A redox sensor in protein kinase A regulatory subunit Iα regulates vasodilation and protects against hypertension

The regulatory RIα subunit of type I protein kinase A (PKARIα) can be oxidized to an interprotein disulfide homodimer, linking cellular oxidant signals with downstream phosphorylation-mediated physiological regulation. Although PKA and oxidants each have well-established roles in vasodilation and blood pressure lowering, whether the oxidation of RIα to the disulfide state regulates these physiological processes is unknown. Here, we demonstrate that PKARIα contains a thiol redox sensor, the oxidation state of which is dynamic and modulates systemic arterial blood pressure by regulating oxidant-induced vasodilation. Mesenteric or carotid arteries, penetrating cerebrovascular arterioles or aortae isolated from 'redox-dead' Cys17Ser PKARIα knock-in mice that are resistant to disulfide-dimer formation demonstrate enhanced responses to vasoconstrictors and impaired vasodilation induced by oxidants, but not nitric oxide or cAMP elevation, compared to wild-type preparations. Although administration of angiotensin II increased vasoconstriction, this pro-oxidant vasopressor hormone concomitantly increased vasodilatory disulfide-PKARIα and limited the development of hypertension and pressure-induced cardiac hypertrophy in a mouse model. These observations indicate a role for disulfide-PKARIα in vasodilation; however, the knock-in mice were normotensive with blood pressure similar to that of wild-type controls. Heart rate variability analysis showed that the knock-in mice had a lower low-to-high frequency ratio than wild-type mice, pointing to reduced sympathetic activity in the 'redox-dead' transgenic mice. This was corroborated biochemically by lower norepinephrine levels in renal and cardiac tissues of the knock-in mice. Reduced sympathetic activity would explain why the PKARIα knock-in animals are not hypertensive despite their arteries having enhanced constrictor responses to vasopressors. Together, the data obtained in this study provide strong evidence that oxidation of PKARIα couples to arterial dilation and mitigates blood pressure increases, highlighting this kinase as a potential new target for thiol-based therapeutics to treat systemic hypertension.