Zhou, ChaomingRamaswamy, Swarna S.Johnson, Derrick E.Vitturi, Dario A.Schopfer, Franciso J.Freeman, Bruce A.Hudmon, AndyLevitan, Edwin S.2016-08-102016-08-102016Zhou, C., Ramaswamy, S. S., Johnson, D. E., Vitturi, D. A., Schopfer, F. J., Freeman, B. A., … Levitan, E. S. (2016). Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling. Scientific Reports, 6, 23416. http://doi.org/10.1038/srep234162045-2322https://hdl.handle.net/1805/10639Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) oxidation controls excitability and viability. While hydrogen peroxide (H2O2) affects Ca(2+)-activated CaMKII in vitro, Angiotensin II (Ang II)-induced CaMKIIδ signaling in cardiomyocytes is Ca(2+) 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 Ca(2+)/CaM. Remarkably, this apokinase stimulation persists after mutating known oxidation targets (M281, M282, C290), suggesting a novel mechanism for increasing baseline Ca(2+)-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 CaMKIIδ 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.en-USAttribution 3.0 United StatesCardiac hypertrophyCellular neuroscienceCalcium-Calmodulin-Dependent Protein Kinase Type 2Angiotensin IIArticle