HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Nitric oxide-dependent activation of CaMKII increases diastolic sarcoplasmic reticulum calcium release in cardiac myocytes in response to adrenergic stimulation.

Abstract
Spontaneous calcium waves in cardiac myocytes are caused by diastolic sarcoplasmic reticulum release (SR Ca(2+) leak) through ryanodine receptors. Beta-adrenergic (β-AR) tone is known to increase this leak through the activation of Ca-calmodulin-dependent protein kinase (CaMKII) and the subsequent phosphorylation of the ryanodine receptor. When β-AR drive is chronic, as observed in heart failure, this CaMKII-dependent effect is exaggerated and becomes potentially arrhythmogenic. Recent evidence has indicated that CaMKII activation can be regulated by cellular oxidizing agents, such as reactive oxygen species. Here, we investigate how the cellular second messenger, nitric oxide, mediates CaMKII activity downstream of the adrenergic signaling cascade and promotes the generation of arrhythmogenic spontaneous Ca(2+) waves in intact cardiomyocytes. Both SCaWs and SR Ca(2+) leak were measured in intact rabbit and mouse ventricular myocytes loaded with the Ca-dependent fluorescent dye, fluo-4. CaMKII activity in vitro and immunoblotting for phosphorylated residues on CaMKII, nitric oxide synthase, and Akt were measured to confirm activity of these enzymes as part of the adrenergic cascade. We demonstrate that stimulation of the β-AR pathway by isoproterenol increased the CaMKII-dependent SR Ca(2+) leak. This increased leak was prevented by inhibition of nitric oxide synthase 1 but not nitric oxide synthase 3. In ventricular myocytes isolated from wild-type mice, isoproterenol stimulation also increased the CaMKII-dependent leak. Critically, in myocytes isolated from nitric oxide synthase 1 knock-out mice this effect is ablated. We show that isoproterenol stimulation leads to an increase in nitric oxide production, and nitric oxide alone is sufficient to activate CaMKII and increase SR Ca(2+) leak. Mechanistically, our data links Akt to nitric oxide synthase 1 activation downstream of β-AR stimulation. Collectively, this evidence supports the hypothesis that CaMKII is regulated by nitric oxide as part of the adrenergic cascade leading to arrhythmogenesis.
AuthorsJerry Curran, Lifei Tang, Steve R Roof, Sathya Velmurugan, Ashley Millard, Stephen Shonts, Honglan Wang, Demetrio Santiago, Usama Ahmad, Matthew Perryman, Donald M Bers, Peter J Mohler, Mark T Ziolo, Thomas R Shannon
JournalPloS one (PLoS One) Vol. 9 Issue 2 Pg. e87495 ( 2014) ISSN: 1932-6203 [Electronic] United States
PMID24498331 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Adrenergic Agents
  • Enzyme Inhibitors
  • Ryanodine Receptor Calcium Release Channel
  • Nitric Oxide
  • Nitric Oxide Synthase Type I
  • Proto-Oncogene Proteins c-akt
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Isoproterenol
  • Calcium
  • NG-Nitroarginine Methyl Ester
Topics
  • Adrenergic Agents (pharmacology)
  • Animals
  • Blotting, Western
  • Calcium (metabolism)
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
  • Cells, Cultured
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Isoproterenol (pharmacology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Cardiac (cytology, drug effects, metabolism)
  • NG-Nitroarginine Methyl Ester (pharmacology)
  • Nitric Oxide (metabolism)
  • Nitric Oxide Synthase Type I (antagonists & inhibitors, deficiency, genetics)
  • Phosphorylation (drug effects)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Rabbits
  • Ryanodine Receptor Calcium Release Channel (metabolism)
  • Sarcoplasmic Reticulum (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: