Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling

Chaoming Zhou, Swarna S. Ramaswamy, Derrick E. Johnson, Dario A. Vitturi, Franciso J. Schopfer, Bruce A. Freeman, Andy Hudmon, Edwin S. Levitan

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Ca2+/calmodulin-dependent protein kinase II (CaMKII) oxidation controls excitability and viability. While hydrogen peroxide (H2O2) affects Ca2+-activated CaMKII in vitro, Angiotensin II (Ang II)-induced CaMKIIIδ signaling in cardiomyocytes is Ca2+ independent and requires NADPH oxidase-derived superoxide, but not its dismutation product H2O2. To better define the biological regulation of CaMKII activation and signaling by Ang II, we evaluated the potential for peroxynitrite (ONOO-) to mediate CaMKII activation and downstream Kv4.3 channel mRNA destabilization by Ang II. In vitro experiments show that ONOO- oxidizes and modestly activates pure CaMKII in the absence of Ca2+/CaM. Remarkably, this apokinase stimulation persists after mutating known oxidation targets (M281, M282, C290), suggesting a novel mechanism for increasing baseline Ca2+-independent CaMKII activity. The role of ONOO- in cardiac and neuronal responses to Ang II was then tested by scavenging ONOO- and preventing its formation by inhibiting nitric oxide synthase. Both treatments blocked Ang II effects on Kv4.3, tyrosine nitration and CaMKIIIδ oxidation and activation. Together, these data show that ONOO- participates in Ang II-CaMKII signaling. The requirement for ONOO- in transducing Ang II signaling identifies ONOO-, which has been viewed as a reactive damaging byproduct of superoxide and nitric oxide, as a mediator of GPCR-CaMKII signaling.

Original languageEnglish (US)
Article number23416
JournalScientific reports
StatePublished - Apr 15 2016

ASJC Scopus subject areas

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    Zhou, C., Ramaswamy, S. S., Johnson, D. E., Vitturi, D. A., Schopfer, F. J., Freeman, B. A., Hudmon, A., & Levitan, E. S. (2016). Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling. Scientific reports, 6, [23416].