Gap junctions are responsible for intercellular propagation of electrical signals throughout the heart. Downregulation of connexin43 (Cx43), the predominant connexin expressed in mammalian ventricular tissue, is thought to underlie conduction abnormalities that may lead to lethal ventricular arrhythmias in diseased hearts. Expression of CA5 in normal ventricles is thought to be limited and of unknown physiologic relevance. We have obtained exciting new evidence of dramatic, focal increases in Cx45 expression in human hearts from patients with end-stage heart failure who are at high risk for developing malignant ventricular arrhythmias and sudden cardiac death. The present proposal will focus on a novel hypothesis that Cx45 is upregulated in a patchy, heterogeneous distribution in the diseased heart, which contributes to reduced intercellular coupling, discontinuous propagation and induction of arrhythmias.
The specific aims are (1) to delineate the effects of Cx45 expression and Cx45/Cx43 stoichiometries on gap junction structure and distribution, (2) to delineate specific electrophysiologic parameters that are disrupted or induced by overexpression of CA5 and (3) to demonstrate that upregulation of CA5 in disease states is a major determinant of arrhythmogenesis. Structural and electrophysiologic responses to heart failure induced by pressure overload, and myocardial infarction induced by coronary artery occlusion, will be assessed in transgenic mice overexpressing Cx45 in the presence or absence of genetic deficiency in Cx43. Experimental methods used for assessing structural and electrical remodeling will include confocal immunohistochemistry, fight and electron microscopy, in vivo and in vitro electrophysiology studies and ambulatory ECG monitoring. These studies will provide novel fundamental insights into remodeling of coupling proteins that determine cellular mechanisms of arrhythmogenesis and the potential importance of intercellular coupling for development of new therapeutic strategies aimed at reducing the risk of sudden death associated with myocardial infarction and heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066350-03
Application #
6527703
Study Section
Special Emphasis Panel (ZHL1-CSR-O (S1))
Program Officer
Lathrop, David A
Project Start
2000-09-30
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$346,500
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Wang, Jian-Guo; Williams, Julie C; Davis, Beckley K et al. (2011) Monocytic microparticles activate endothelial cells in an IL-1?-dependent manner. Blood 118:2366-74
Zhang, Yan; Kanter, Evelyn M; Yamada, Kathryn A (2010) Remodeling of cardiac fibroblasts following myocardial infarction results in increased gap junction intercellular communication. Cardiovasc Pathol 19:e233-40
Zhang, Yan; Wang, Hongtao; Kovacs, Attila et al. (2010) Reduced expression of Cx43 attenuates ventricular remodeling after myocardial infarction via impaired TGF-beta signaling. Am J Physiol Heart Circ Physiol 298:H477-87
Hund, Thomas J; Decker, Keith F; Kanter, Evelyn et al. (2008) Role of activated CaMKII in abnormal calcium homeostasis and I(Na) remodeling after myocardial infarction: insights from mathematical modeling. J Mol Cell Cardiol 45:420-8
Yamada, Kathryn A (2008) A change of heart: heterogeneous remodeling in heart failure. Heart Rhythm 5:1186-8
Zhang, Yan; Kanter, Evelyn M; Laing, James G et al. (2008) Connexin43 expression levels influence intercellular coupling and cell proliferation of native murine cardiac fibroblasts. Cell Commun Adhes 15:289-303
Hund, Thomas J; Lerner, Deborah L; Yamada, Kathryn A et al. (2007) Protein kinase Cepsilon mediates salutary effects on electrical coupling induced by ischemic preconditioning. Heart Rhythm 4:1183-93
Sundset, R; Ytrehus, K; Zhang, Y et al. (2007) Repeated simulated ischemia and protection against gap junctional uncoupling. Cell Commun Adhes 14:239-49

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