Redox-sensitive calcium/calmodulin-dependent protein kinase IIα in angiotensin II intra-neuronal signaling and hypertension

Dysregulation of brain angiotensin II (AngII) signaling results in modulation of neuronal ion channel activity, an increase in neuronal firing, enhanced sympathoexcitation, and subsequently elevated blood pressure. Studies over the past two decades have shown that these AngII responses are mediated, in part, by reactive oxygen species (ROS). However, the redox-sensitive target(s) that are directly acted upon by these ROS to execute the AngII pathophysiological responses in neurons remain unclear. Calcium/calmodulin-dependent protein kinase II (CaMKII) is an AngII-activated intra-neuronal signaling protein, which has been suggested to be redox sensitive as overexpressing the antioxidant enzyme superoxide dismutase attenuates AngII-induced activation of CaMKII. Herein, we hypothesized that the neuronal isoform of CaMKII, CaMKII-alpha (CaMKII alpha), is a redox-sensitive target of AngII, and that mutation of potentially redox-sensitive amino acids in CaMKII alpha influences AngIImediated intra-neuronal signaling and hypertension. Adenoviral vectors expressing wild-type mouse CaMKII alpha (Ad.wtCaMKII alpha) or mutant CaMKII alpha (Ad.mutCaMKII alpha) with C280A and M281V mutations were generated to overexpress either CaMKII alpha isoform in mouse catecholaminergic cultured neurons (CATH.a) or in the brain subfornical organ (SFO) of hypertensive mice. Overexpressing wtCaMKII alpha exacerbated AngII pathophysiological responses as observed by a potentiation of AngII-induced inhibition of voltage-gated K+ current, enhanced in vivo pressor response following intracerebroventricular injection of AngII, and sensitization to chronic peripheral infusion of AngII resulting in a more rapid increase in blood pressure. In contrast, expressing the mutant CaMKII alpha in CATH.a neurons or the SFO failed to intensify these AngII responses. Taken together, these data identify neuronal CaMKII alpha as a redox-sensitive signaling protein that contributes to AngII-induced neuronal activation and hypertension.