Rhythmic heartbeat requires the proper development of the cardiac conduction system. This specialized cardiac tissue consists of distinct subcomponents, including the pacemaking sinoatrial (SA) node, fast conducting internodal tract (INT), slow conducting atrioventricular (AV) node, AV-bundles, and fast conducting Purkinje fibers. In human, a defect in the organization of the INT and AV-node can be a cause of atrial fibrillation and AV block, respectively, with consequent significant cardiovascular morbidity and mortality. Little is known about how these distinct conducting elements are induced, patterned, and integrated into a complete CCS network. We have previously shown that the vascular cytokine endothelin (ET) is derived from endocardial and arterial endothelial cells and induce ventricular myocytes to differentiate into fast conducting Purkinje fibers. However, mechanisms that induce and pattern other CCS subcomponents, such as the INT and AV-node, remain largely elusive. Our preliminary data show that endothelin converting enzyme-1 (ECE1), which is necessary for production of biologically active ET from its precursor, and G protein-coupled ET-receptors (ETRs) are both expressed in the atrium of the embryonic chick heart. Furthermore, a unique set of genes that are expressed by fast conducting Purkinje fibers occurs along ECE1-positive endocardial cells in the atrium. By contrast, no fast conducting cell-type genes are detected at the AV-junction despite the highest expression of ECE1 as well as ET-precursor. Importantly, we have found that ETR expression is absent at the AV-junction. These data lead to the two central hypotheses: (1) Fast conducting atrial INT and ventricular Purkinje systems share common features and arise through the activity of a common inducing signal;and (2) The absence of ETRs at the AV-junction suppresses the responsiveness of myocytes to ET signal, thereby creating a zone free of fast conducting cell differentiation. This proposal will test these hypothesis experimentally and will provide the first molecular basis for identifying cells unique to the INT (Aim 1), the ability of embryonic atrial myocytes to respond to inductive signals and enter a fast conduction cell fate (Aim 2), and molecular mechanisms that generate a zone free of fast conducting cell differentiation in the embryonic heart (Aim 3). The outcome of this study will serve as the basis for the understanding of normal and aberrant INT formation and for addressing a mechanism that defines slow conduction cell differentiation exclusively to the AV-junction.

Public Health Relevance

Conduction defects, including atrial fibrillation and AV-block, affect millions people in the US, but current treatments are limited to pharmacotherapy, radiofrequency ablation, and implantable devices. The lack of effective treatment options contributes to the continued prevalence of arrhythmic disease. The proposed study will explore the molecular mechanisms that regulate formation of these essential cardiac tissues and may provide a basis for future therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093566-05
Application #
8309486
Study Section
Special Emphasis Panel (ZRG1-CVS-D (02))
Program Officer
Schramm, Charlene A
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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