ArticlePloS one2014
Nitric oxide-dependent activation of CaMKII increases diastolic sarcoplasmic reticulum calcium release in cardiac myocytes in response to adrenergic stimulation.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 83 citations in OpenAlex.
- Trial
- Annexin A4 Deficient Ventricular Myocytes Display Advanced Hypertrophy and Electrical Remodeling With Chronic β-Adrenoceptor Stimulation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe Cardiomyopathy.Journal of the American Heart Association · 2025Article
- Molecular and cellular neurocardiology in heart disease.The Journal of physiology · 2025Review
- S-nitrosylation of cardiac myocyte proteins may underlie sex differences in cardiac disease.Frontiers in physiology · 2025Review
- Article
- Gasotransmitters and noble gases in cardioprotection: unraveling molecular pathways for future therapeutic strategies.Basic research in cardiology · 2024Review
- USP38 exacerbates pressure overload-induced left ventricular electrical remodeling.Molecular medicine (Cambridge, Mass.) · 2024Article
- Nitric Oxide: Physiological Functions, Delivery, and Biomedical Applications.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Review
- Nitrosylation of cardiac CaMKII at Cys290 mediates mechanical afterload-induced increases in CaThe Journal of physiology · 2022Article
- Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes.Antioxidants (Basel, Switzerland) · 2021Article
- Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling.Cells · 2021Article
- Estimating ectopic beat probability with simplified statistical models that account for experimental uncertainty.PLoS computational biology · 2021Article
- Review
- Emergence of Mechano-Sensitive Contraction Autoregulation in Cardiomyocytes.Life (Basel, Switzerland) · 2021Article
- CaMKII Inhibition is a Novel Therapeutic Strategy to Prevent Diabetic Cardiomyopathy.Frontiers in pharmacology · 2021Review
- CaMKII in Regulation of Cell Death During Myocardial Reperfusion Injury.Frontiers in molecular biosciences · 2021Review
- Nitric oxide modulates cardiomyocyte pH control through a biphasic effect on sodium/hydrogen exchanger-1.Cardiovascular research · 2020Article
- Muscarinic-dependent phosphorylation of the cardiac ryanodine receptor by protein kinase G is mediated by PI3K-AKT-nNOS signaling.The Journal of biological chemistry · 2020Article
- Hyperglycemia Acutely Increases Cytosolic Reactive Oxygen Species viaCirculation research · 2020Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
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.
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Registered trials
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