Exciting recent evidence supports a view that sinoatrial node (SAN) cardiac pacemaker cells cause heart rate increases by enhancement of sarcoplasmic reticulum (SR) Ca2+ release and augmentation of depolarizing inward current carried by the sarcolemmal Na+/Ca2+ exchanger (NCX). Proteins dedicated to excitation-contraction coupling and cellular Ca2+ cycling in contracting cardiomyocytes are preserved in SAN cells, and our studies show SAN cells and ventricular myocytes have similar SR Ca2+ content, indexed for cell membrane capacitance, despite the fact that SAN cells exhibit minimal mechanical activity. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is a serine- threonine kinase that regulates the SR-associated Ca2+ homeostatic proteins, phospholamban (PLN) and ryanodine receptors (RyR). Our new data support a view that CaMKII plays a central role in ? adrenergic receptor (?AR) mediated SAN 'fight or flight'physiological responses. Furthermore, under conditions of excessive, pathological ?AR stimulation, CaMKII inhibition enhances SAN cell survival and protects against SAN arrhythmias. We hypothesize that 1) CaMKII regulates SR Ca2+ uptake and release as part of a cellular mechanism for physiological SAN responses to ?AR stimulation;2) CaMKII inhibition protects against SAN arrhythmias, SAN cell death and hypertrophy by preventing SR Ca2+ overload and reducing SR Ca2+ leak;3) inward NCX current is the major sarcolemmal target activated by SR Ca2+ release, leading to enhanced phase 4 cell membrane depolarization and faster heart rates. Our laboratory has adapted and developed new methods for reliably isolating mouse and rabbit SAN cells, and performing in vivo viral gene transfer to the SAN and in vitro viral gene transfer to cultured SAN cells. These innovative approaches will allow us to comprehensively test the role of CaMKII, SR Ca2+ and NCX in cardiac pacing.

Public Health Relevance

Relevant to Public Health Sinoatrial nodal (SAN) cardiac pacemaker failure is a significant cause of morbidity and mortality in the United States. We spend over 2 billion dollars on permanent, surgically-implanted pacemakers annually. Pacemakers are a successful but highly imperfect therapy that do not treat the underlying disease and are subject to mechanical failure, infection and require repetitive surgical replacement. Thus, improved, non-invasive therapies for SAN failure would produce important public health benefits for Americans. Furthermore, SAN failure is a frequent finding in patients with atrial fibrillation and is associated with increased mortality in heart failure. Despite the clear importance of these specialized SAN cells, critical knowledge gaps remain for understanding SAN cell signaling and the coupling between intracellular Ca2+ and SAN cell electrical outputs. Improved understanding of SAN cell biology is a necessary first step to developing improved therapies for regulating SAN function and extending SAN survival. Our proposal focuses on the role of CaMKII as a central, but neglected, signal for inducing SAN disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096652-04
Application #
8269846
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Krull, Holly
Project Start
2009-07-15
Project End
2013-08-18
Budget Start
2012-05-01
Budget End
2013-08-18
Support Year
4
Fiscal Year
2012
Total Cost
$371,250
Indirect Cost
$123,750
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Mesubi, Olurotimi O; Anderson, Mark E (2016) Atrial remodelling in atrial fibrillation: CaMKII as a nodal proarrhythmic signal. Cardiovasc Res 109:542-57
Wu, Yuejin; Valdivia, Héctor H; Wehrens, Xander H T et al. (2016) A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca2+ Clock. Circ Arrhythm Electrophysiol 9:e003180
Gao, Zhan; Sierra, Ana; Zhu, Zhiyong et al. (2016) Loss of ATP-Sensitive Potassium Channel Surface Expression in Heart Failure Underlies Dysregulation of Action Potential Duration and Myocardial Vulnerability to Injury. PLoS One 11:e0151337
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Sommese, Leandro; Valverde, Carlos A; Blanco, Paula et al. (2016) Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca(2+) release events in a rodent model of early stage diabetes: The arrhythmogenic substrate. Int J Cardiol 202:394-406
Wu, Yuejin; Rasmussen, Tyler P; Koval, Olha M et al. (2015) The mitochondrial uniporter controls fight or flight heart rate increases. Nat Commun 6:6081
Wu, Yuejin; Rasmussen, Tyler P; Koval, Olha M et al. (2015) Corrigendum: The mitochondrial uniporter controls fight or flight heart rate increases. Nat Commun 6:7241
Anderson, Mark E (2015) Oxidant stress promotes disease by activating CaMKII. J Mol Cell Cardiol 89:160-7
Rasmussen, Tyler P; Wu, Yuejin; Joiner, Mei-ling A et al. (2015) Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. Proc Natl Acad Sci U S A 112:9129-34

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