TY - JOUR
T1 - Redox-sensitive calcium/calmodulin-dependent protein kinase IIα in angiotensin II intra-neuronal signaling and hypertension
T2 - Redox-sensitive neuronal CaMKIIα in AngII hypertension
AU - Basu, Urmi
AU - Case, Adam J.
AU - Liu, Jinxu
AU - Tian, Jun
AU - Li, Yu Long
AU - Zimmerman, Matthew C.
N1 - Funding Information:
This study was supported by a National Institutes of Health Grant R01-HL103942 (M.C. Zimmerman). We thank the University of Nebraska Medical Center Advanced Microscopy Core Facility for providing assistance with confocal microscopy. This Core facility receives partial support from the National Institute of General Medical Sciences INBRE - P20 GM103427 and COBRE - P30 GM106397 grants, as well as support from the National Cancer Institute for The Fred & Pamela Buffett Cancer Center Support Grant- P30 CA036727 , and the Nebraska Research Initiative. This publication's contents and interpretations are the sole responsibility of the authors.
Funding Information:
This study was supported by a National Institutes of Health Grant R01-HL103942 (M.C. Zimmerman). We thank the University of Nebraska Medical Center Advanced Microscopy Core Facility for providing assistance with confocal microscopy. This Core facility receives partial support from the National Institute of General Medical Sciences INBRE - P20 GM103427 and COBRE - P30 GM106397 grants, as well as support from the National Cancer Institute for The Fred & Pamela Buffett Cancer Center Support Grant- P30 CA036727, and the Nebraska Research Initiative. This publication's contents and interpretations are the sole responsibility of the authors.
Publisher Copyright:
© 2019 The Authors
PY - 2019/10
Y1 - 2019/10
N2 - 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 (CaMKIIα), is a redox-sensitive target of AngII, and that mutation of potentially redox-sensitive amino acids in CaMKIIα influences AngII-mediated intra-neuronal signaling and hypertension. Adenoviral vectors expressing wild-type mouse CaMKIIα (Ad.wtCaMKIIα) or mutant CaMKIIα (Ad.mutCaMKIIα) with C280A and M281V mutations were generated to overexpress either CaMKIIα isoform in mouse catecholaminergic cultured neurons (CATH.a) or in the brain subfornical organ (SFO) of hypertensive mice. Overexpressing wtCaMKIIα 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 CaMKIIα in CATH.a neurons or the SFO failed to intensify these AngII responses. Taken together, these data identify neuronal CaMKIIα as a redox-sensitive signaling protein that contributes to AngII-induced neuronal activation and hypertension.
AB - 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 (CaMKIIα), is a redox-sensitive target of AngII, and that mutation of potentially redox-sensitive amino acids in CaMKIIα influences AngII-mediated intra-neuronal signaling and hypertension. Adenoviral vectors expressing wild-type mouse CaMKIIα (Ad.wtCaMKIIα) or mutant CaMKIIα (Ad.mutCaMKIIα) with C280A and M281V mutations were generated to overexpress either CaMKIIα isoform in mouse catecholaminergic cultured neurons (CATH.a) or in the brain subfornical organ (SFO) of hypertensive mice. Overexpressing wtCaMKIIα 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 CaMKIIα in CATH.a neurons or the SFO failed to intensify these AngII responses. Taken together, these data identify neuronal CaMKIIα as a redox-sensitive signaling protein that contributes to AngII-induced neuronal activation and hypertension.
KW - Angiotensin II
KW - Calcium/calmodulin-dependent protein kinase IIα
KW - Hypertension
KW - Neurons
KW - Reactive oxygen species
KW - Redox signaling
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U2 - 10.1016/j.redox.2019.101230
DO - 10.1016/j.redox.2019.101230
M3 - Article
C2 - 31175066
AN - SCOPUS:85066452691
VL - 27
JO - Redox Biology
JF - Redox Biology
SN - 2213-2317
M1 - 101230
ER -