Activation of the renin-angiotensin system (RAS) is associated with increased cardiovascular death. A critical component of this system is angiotensin converting enzyme (ACE), which cleaves angiotensin I to angiotensin II (Angll). In humans, increased Angll levels are associated with an increased ventricular arrhythmic risk. Nevertheless, the reasons for the increased risk are unclear. One critical effect of RAS activation is Angll-induced oxidative stress mediated, in part, by increased NADPH oxidase activity. We hypothesized that oxidative stress caused by Angll induced cardiac arrhythmias. To investigate this, we developed a cardiac-restricted ACE overexpression mouse (ACE 8/8) that showed an increased risk of sudden death in the absence of heart failure or structural heart disease. Intracardiac recordings demonstrate poor conduction and various forms of AV nodal block. Ventricular pacing readily induced ventricular tachycardia. This phenotype is associated with reductions in cardiac sodium channels. We have developed preliminary data that Angll-mediated oxidative stress activates the transcription factor NFkB resulting in downregulation of the cardiac sodium channel. In this proposal, we hypothesize that increased Angll leads to oxidative stress which in-turn alters sodium channel transcription through NFkB activation. An altered ion channel level contributes to the ACE 8/8 mouse arrhythmic phenotype. This proposal is a plan to dissect the steps in this putative cascade and to identify which are proximate causes, which are upstream events, and which are associated but not causative steps. In each aim, we will establish to what extent measures of the sodium channel, NFkB activation, oxidative stress, and arrhythmic risk are altered by the disruptions in the proposed signaling cascade. Specific Objectives.
Specific aim 1 : To establish to what extent Angll-mediated signaling is responsible for the sodium channel regulation in our ACE overexpression model.
Specific aim 2 : To establish to what extent NADPH oxidase activation is responsible for the sodium channel regulation in our ACE overexpression model.
Specific aim 3 : To establish to what extent increased NFkB activation is responsible for the sodium channel regulation in our ACE overexpression model. This application presents a novel hypothesis about why RAS activation causes arrhythmias, contributing to atrial fibrillation (AF) and heart failure (HF)-associated sudden death. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL085558-01A1
Application #
7319963
Study Section
Special Emphasis Panel (ZRG1-CVS-F (02))
Program Officer
Przywara, Dennis
Project Start
2007-08-01
Project End
2007-11-30
Budget Start
2007-08-01
Budget End
2007-11-30
Support Year
1
Fiscal Year
2007
Total Cost
$333,529
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Rutledge, Cody A; Ng, Fu Siong; Sulkin, Matthew S et al. (2014) c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction. J Am Coll Cardiol 63:928-34
Yang, Kai-Chien; Rutledge, Cody A; Mao, Mao et al. (2014) Caveolin-1 modulates cardiac gap junction homeostasis and arrhythmogenecity by regulating cSrc tyrosine kinase. Circ Arrhythm Electrophysiol 7:701-10
Jeong, Euy-Myoung; Monasky, Michelle M; Gu, Lianzhi et al. (2013) Tetrahydrobiopterin improves diastolic dysfunction by reversing changes in myofilament properties. J Mol Cell Cardiol 56:44-54
Lovelock, Joshua D; Monasky, Michelle M; Jeong, Euy-Myoung et al. (2012) Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity. Circ Res 110:841-50
Liang, Yongliang; Roede, James R; Dikalov, Sergey et al. (2012) Determination of ebselen-sensitive reactive oxygen metabolites (ebROM) in human serum based upon N,N'-diethyl-1,4-phenylenediamine oxidation. Clin Chim Acta 414:1-6
Simpson, David L; Boyd, Nolan L; Kaushal, Sunjay et al. (2012) Use of human embryonic stem cell derived-mesenchymal cells for cardiac repair. Biotechnol Bioeng 109:274-83
Jeong, Euy-Myoung; Liu, Man; Sturdy, Megan et al. (2012) Metabolic stress, reactive oxygen species, and arrhythmia. J Mol Cell Cardiol 52:454-63
Negi, Smita I; Jeong, Euy-Myoung; Shukrullah, Irfan et al. (2012) Association of low plasma adiponectin with early diastolic dysfunction. Congest Heart Fail 18:187-91
Sovari, Ali A; Iravanian, Shahriar; Dolmatova, Elena et al. (2011) Inhibition of c-Src tyrosine kinase prevents angiotensin II-mediated connexin-43 remodeling and sudden cardiac death. J Am Coll Cardiol 58:2332-9
Sovari, Ali A; Bonini, Marcelo G; Dudley, Samuel C (2011) Effective antioxidant therapy for the management of arrhythmia. Expert Rev Cardiovasc Ther 9:797-800

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