Endothelial CaMKII as a regulator of eNOS activity and NO-mediated vasoreactivity

Shubha Murthy, Olha M. Koval, Juan M. Ramiro Diaz, Santosh Kumar, Daniel Nuno, Jason A. Scott, Chantal Allamargot, Linda J. Zhu, Kim Broadhurst, Velarchana Santhana, William J. Kutschke, Kaikobad Irani, Kathryn G. Lamping, Isabella M. Grumbach

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase important in transducing intracellular Ca2+ signals. While in vitro data regarding the role of CaMKII in the regulation of endothelial nitric oxide synthase (eNOS) are contradictory, its role in endothelial function in vivo remains unknown. Using two novel transgenic models to express CaMKII inhibitor peptides selectively in endothelium, we examined the effect of CaMKII on eNOS activation, NO production, vasomotor tone and blood pressure. Under baseline conditions, CaMKII activation was low in the aortic wall. Consistently, systolic and diastolic blood pressure, heart rate and plasma NO levels were unaltered by endothelial CaMKII inhibition. Moreover, endothelial CaMKII inhibition had no significant effect on NO-dependent vasodilation. These results were confirmed in studies of aortic rings transduced with adenovirus expressing a CaMKII inhibitor peptide. In cultured endothelial cells, bradykinin treatment produced the anticipated rapid influx of Ca2+ and transient CaMKII and eNOS activation, whereas CaMKII inhibition blocked eNOS phosphorylation on Ser-1179 and dephosphorylation at Thr-497. Ca2+/CaM binding to eNOS and resultant NO production in vitro were decreased under CaMKII inhibition. Our results demonstrate that CaMKII plays an important role in transient bradykinin-driven eNOS activation in vitro, but does not regulate NO production, vasorelaxation or blood pressure in vivo under baseline conditions.

Original languageEnglish (US)
Article numbere0186311
JournalPloS one
Volume12
Issue number10
DOIs
StatePublished - Oct 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint Dive into the research topics of 'Endothelial CaMKII as a regulator of eNOS activity and NO-mediated vasoreactivity'. Together they form a unique fingerprint.

  • Cite this

    Murthy, S., Koval, O. M., Ramiro Diaz, J. M., Kumar, S., Nuno, D., Scott, J. A., Allamargot, C., Zhu, L. J., Broadhurst, K., Santhana, V., Kutschke, W. J., Irani, K., Lamping, K. G., & Grumbach, I. M. (2017). Endothelial CaMKII as a regulator of eNOS activity and NO-mediated vasoreactivity. PloS one, 12(10), [e0186311]. https://doi.org/10.1371/journal.pone.0186311