title: Oxidized CaMKII causes cardiac sinus node dysfunction in mice.
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.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Paari Dominic
authors.initials: PD
authors.lastname: Swaminathan
authors.forename: Anil
authors.initials: A
authors.lastname: Purohit
authors.forename: Siddarth
authors.initials: S
authors.lastname: Soni
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.forename: Madhu V
authors.initials: MV
authors.lastname: Singh
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Glukhov
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.forename: B Julie
authors.initials: BJ
authors.lastname: He
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Luczak
authors.forename: Mei-ling A
authors.initials: ML
authors.lastname: Joiner
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.forename: Jinying
authors.initials: J
authors.lastname: Yang
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Donahue
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Grumbach
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ogawa
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.forename: Igor
authors.initials: I
authors.lastname: Efimov
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D004285:Dogs; D004562:Electrocardiography / Q000379:methods; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000235:genetics; D010100:Oxygen / Q000737:chemistry*; D017382:Reactive Oxygen Species; D012804:Sick Sinus Syndrome / Q000235:genetics* / Q000378:metabolism; D012849:Sinoatrial Node / Q000473:pathology*
chemical_list: D015415:Biomarkers; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010100:Oxygen