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Am J Physiol Heart Circ Physiol (February 9, 2007). doi:10.1152/ajpheart.01247.2006
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Submitted on November 15, 2006
Accepted on February 8, 2007

iNOS Regulation by Calcium/Calmodulin-Dependent Protein Kinase II in Vascular Smooth Muscle

Rachel J Jones1, David Jourd'heuil1, John C Salerno2, Susan ME Smith3, and Harold A Singer1*

1 Center for Cardiovascular Sciences, Albany Medical Center, 12208, New York, United States
2 Biological and Physical Sciences, Kennesaw State University, Kennesaw, Georgia, United States
3 Cardiology, Emory University, Atlanta, Georgia, United States

* To whom correspondence should be addressed. E-mail: singerh{at}mail.amc.edu.

iNOS expression is regulated transcriptionally in response to cytokine induction and post-translationally by palmitoylation and trafficking into perinuclear aggresomes. We investigated the effects of multifunctional calcium/calmodulin-dependent protein kinase II protein kinase (CaMKII) on iNOS trafficking in cultured rat aortic vascular smooth muscle cells (VSMC). Immunofluorescence and confocal microscopy demonstrated colocalization of iNOS and CaMKII{delta}2 with a perinuclear distribution and concentration in aggresome-like structures identified by colocalization with {gamma}-tubulin. Furthermore, CaMKII{delta}2 coimmunoprecipitated with iNOS and pre-incubation with KN-93 (a CaMKII inhibitor) facilitated this association. Addition of Ca2+ mobilizing stimuli expected to activate CaMKII; a purinergic agonist (UTP) or calcium ionophore (ionomycin), caused a general redistribution of iNOS from cytosolic to membrane and nuclear fractions. Similarly, adenoviral expression of a constitutively active CaMKII{delta}2 mutant altered iNOS localization, shifting iNOS from the cytosolic fraction. Suppression of CaMKII{delta}2 using an adenovirus expressing a short hairpin siRNA increased nuclear iNOS localization in resting cells, but inhibited ionomycin-induced translocation of iNOS to the nucleus. Following addition of these chronic and acute CaMKII modulators there were fewer aggresome-like structures containing iNOS. All of the treatments that chronically affected CaMKII activity or expression significantly inhibited iNOS specific activity following cytokine induction. The data shows the regulation of a complex by CaMKII{delta}2 via activation of CaMKII{delta}2 or the loss of the kinase. This break in the complex causes a mislocalization of iNOS and abrogates iNOS activity. The results suggest that CaMKII{delta}2 may be an important regulator of iNOS trafficking and activity in VSMCs.




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