Journal article
Oxidized CaMKII causes cardiac sinus node dysfunction in mice
The Journal of clinical investigation, Vol.121(8), pp.3277-3288
08/2011
DOI: 10.1172/JCI57833
PMCID: PMC3223923
PMID: 21785215
Abstract
Sinus node dysfunction (SND) is a major public health problem that is associated with sudden cardiac death and requires surgical implantation of artificial pacemakers. However, little is known about the molecular and cellular mechanisms that cause SND. Most SND occurs in the setting of heart failure and hypertension, conditions that are marked by elevated circulating angiotensin II (Ang II) and increased oxidant stress. Here, we show that oxidized calmodulin kinase II (ox-CaMKII) is a biomarker for SND in patients and dogs and a disease determinant in mice. In wild-type mice, Ang II infusion caused sinoatrial nodal (SAN) cell oxidation by activating NADPH oxidase, leading to increased ox-CaMKII, SAN cell apoptosis, and SND. p47-/- mice lacking functional NADPH oxidase and mice with myocardial or SAN-targeted CaMKII inhibition were highly resistant to SAN apoptosis and SND, suggesting that ox-CaMKII-triggered SAN cell death contributed to SND. We developed a computational model of the sinoatrial node that showed that a loss of SAN cells below a critical threshold caused SND by preventing normal impulse formation and propagation. These data provide novel molecular and mechanistic information to understand SND and suggest that targeted CaMKII inhibition may be useful for preventing SND in high-risk patients.
Details
- Title: Subtitle
- Oxidized CaMKII causes cardiac sinus node dysfunction in mice
- Creators
- Paari Dominic Swaminathan - Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAAnil PurohitSiddarth SoniNiels VoigtMadhu V SinghAlexey V GlukhovZhan GaoB Julie HeElizabeth D LuczakMei-ling A JoinerWilliam KutschkeJinying YangJ Kevin DonahueRobert M WeissIsabella M GrumbachMasahiro OgawaPeng-Sheng ChenIgor EfimovDobromir DobrevPeter J MohlerThomas J HundMark E Anderson
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.121(8), pp.3277-3288
- DOI
- 10.1172/JCI57833
- PMID
- 21785215
- PMCID
- PMC3223923
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- R00 HL 096805 / NHLBI NIH HHS R01 HL071140 / NHLBI NIH HHS T32 GM067795 / NIGMS NIH HHS R01 HL079031 / NHLBI NIH HHS R01 HL070250 / NHLBI NIH HHS R01 HL 096652 / NHLBI NIH HHS R01 HL 079031 / NHLBI NIH HHS R01 HL 070250 / NHLBI NIH HHS T32 HL007121 / NHLBI NIH HHS R01 HL 071140 / NHLBI NIH HHS R01 HL096652 / NHLBI NIH HHS RR026293 / NCRR NIH HHS S10 RR026293 / NCRR NIH HHS R00 HL096805 / NHLBI NIH HHS
- Language
- English
- Date published
- 08/2011
- Academic Unit
- Cardiovascular Medicine; Biology; Radiation Oncology; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984094369102771
Metrics
28 Record Views