Graduation Date

Summer 8-14-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cellular & Integrative Physiology

First Advisor

Matthew C. Zimmerman

Abstract

Activation of renin-angiotensin system and elevated levels of circulating and brain angiotensin II (AngII) has been implicated in the pathogenesis of neuro-cardiovascular diseases, such as hypertension and heart failure. In central neurons AngII increases generation of reactive oxygen species (ROS), which in turn regulates neuronal ion channels. Previous studies have demonstrated that ion channels can also be regulated by protein kinases, such as calcium /calmodulin-dependent protein kinase II (CaMKII) as a downstream mediator of AngII signaling. In the heart, CaMKIIδ undergoes oxidation upon AngII stimulation and increased pro-oxidant conditions. However, the exact mechanism by which AngII and ROS regulate CaMKIIα, the major neuronal isoform, in central neurons is unclear. We hypothesized that overexpression of wild-type CaMKIIα in neurons exacerbates the AngII-mediated inhibition of neuronal ion channels and the AngII-induced hypertensive response. Indeed, in mouse catecholaminergic (CATH.a) neurons overexpression of wt-CaMKIIα significantly enhanced the AngII-mediated reduction in K+ current as compared to non-transduced and adenoviral control vector-transduced neurons. Overexpression of wt-CaMKIIα in brain subfornical organ sensitized mice to an immediate increase in blood pressure at an initial subpressor dose of chronic subcutaneous AngII infusion. We further hypothesized that mutation of redox-sensitive cysteine and methionine residues at positions 280 and 281 respectively of CaMKIIα will inhibit the potentiated AngII-signaling in neurons and the rise in blood pressure. Adenovrius-mediated expression of mut-CaMKIIα in CATH.a neurons resulted in a significant restoration of the potentiated AngII-mediated K+ current inhibition observed with wt-CaMKIIα overexpression. Further, mice with mut-CaMKIIα in the brain were prevented from the initial sensitization mechanism following subcutaneous AngII infusion and the peak AngII-induced blood pressure was also significantly attenuated as compared to mice with wt-CaMKIIα overexpression. Together, these studies indicate that redox-regulation of CaMKIIα is an important mechanism in AngII-downstream signaling in neurons and in mediating AngII-induced neurogenic hypertension.

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