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

doi:10.1371/journal.pone.0186311

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

Journal article

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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, …

PloS one, Vol.12(10), pp.e0186311-e0186311

2017

DOI: 10.1371/journal.pone.0186311

PMCID: PMC5653296

PMID: 29059213

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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.

Cell Line

Phosphorylation

Animals

Humans

Nitric Oxide Synthase Type III - metabolism

Nitric Oxide - metabolism

Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism

Details

Title: Subtitle: Endothelial CaMKII as a regulator of eNOS activity and NO-mediated vasoreactivity
Creators: Shubha Murthy - Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa, United States of America
Olha M Koval - Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa, United States of America
Juan M Ramiro Diaz - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Santosh Kumar - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Daniel Nuno - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Jason A Scott - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Chantal Allamargot - Central Microscopy Research Facility, Office of Vice President of Research and Economic Development, University of Iowa, Iowa City, Iowa, United States of America
Linda J Zhu - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Kim Broadhurst - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Velarchana Santhana - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
William J Kutschke - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Kaikobad Irani - Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa, United States of America
Kathryn G Lamping - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Isabella M Grumbach - Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa, United States of America
Resource Type: Journal article
Publication Details: PloS one, Vol.12(10), pp.e0186311-e0186311
DOI: 10.1371/journal.pone.0186311
PMID: 29059213
PMCID: PMC5653296
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science
Grant note: I01 BX000163 / BLRD VA I01 BX002940 / BLRD VA I01 BX000543 / BLRD VA R01 HL108932 / NHLBI NIH HHS I21 RX001561 / RRD VA
Language: English
Date published: 2017
Academic Unit: Core Research Facilities; Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984094386902771

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