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1 Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA
2 Department of Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
3 Department of Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Center for Clinical Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: ggr{at}pitt.edu.
Angiotensin II activation of phospholipase D (PLD) is required for ERK and NAD(P)H oxidase activation, both of which are involved in hypertension. Previous findings demonstrate that angiotensin II stimulates PLD activity through AT1 receptors in a RhoA-dependent
mechanism. Additionally, endogenous AT2 receptors in preglomerular smooth muscle cells attenuate angiotensin II-mediated PLD activity. In the present study we examined the signal transduction mechanisms utilized by endogenous AT2 receptors to modulate angiotensin IIinduced PLD activity through either PLA2 generation of lysophosphatidylethanolamine or G
imediated generation of nitric oxide (NO) and interaction with RhoA. Blockade of AT2 receptors, Gi and NO synthase, but not PLA2, enhanced angiotensin II-mediated PLD activity in cells rich in, but not poor in, AT2 receptors. Moreover, NO donors, a direct activator of guanylyl cyclase and a cGMP analog, but not lysophosphatidylethanolamine inhibited angiotensin II-mediated PLD activity, whereas an inhibitor of guanylyl cyclase augmented angiotensin II induced PLD
activity. AT2 receptor- and NO-mediated attenuation of angiotensin II-induced PLD activity was
completely lost in cells transfected with S188A RhoA, which cannot be phosphorylated on serine 188. Therefore, our data indicates that AT2 receptors activate Gi subsequently stimulating NO
synthase leading to increased soluble guanylyl cyclase activity, generation of cGMP and activation of a protein kinase resulting in phosphorylation of RhoA on serine 188. Furthermore, since AT2 receptors inhibit AT1 receptor signaling to PLD via modulating RhoA activity, AT2 receptor signaling can potentially regulate multiple vasoconstrictive signaling systems through inactivating RhoA.
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