Approximately 6 million people in the United States suffer from chronic angina, a painful sensation resulting from myocardial ischemia in the setting of coronary artery disease. Ischemia is sensed by sensory (afferent) neurons, and activation of these cardiac afferents leads not only to angina, but also produces sympathoexcitation, which is detrimental in the settings of myocardial ischemia and infarction. Still, the underlying mechanisms that cause activation of cardiac sensory neurons are poorly understood. Our goal is to test the hypothesis that acid-sensing ion channels (ASICs) are sensors of cardiac ischemia. This hypothesis is based on previous work that indicates that pH is reduced in the heart in the setting of myocardial ischemia, and our preliminary data that ASICs contribute to acid-evoked currents in cardiac afferent neurons. We will test this hypothesis in three specific aims.
Specific Aim 1 will determine which of the three ASIC proteins contribute to acid-gated ion channels in cardiac sensory neurons from the DRG and nodose ganglia. We have developed a means to specifically label cardiac sensory neurons in vivo so that they can later be identified in isolated culture. This will allow us to identify the ASICs expressed in cardiac afferents, and examine their functional roles using ASIC knockout mice and heterologous expression.
Specific Aim 2 will investigate the contribution of protons and ASICs to sensation of cardiac ischemia in vivo. We will test whether pharmacological and genetic (knockouts) disruption of ASICs alters the response to cardiac acidosis and ischemia in a mouse model.
Specific Aim 3 will test the hypothesis that acid is working in conjunction with other chemical mediators to excite cardiac afferents, and they may activate convergent intracellular signaling mechanisms. This work will provide new insights into the signals and sensors that respond to cardiac ischemia, and define new therapeutic targets and novel approaches for its treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076419-05
Application #
7570710
Study Section
Special Emphasis Panel (ZRG1-CICS (01))
Program Officer
Wang, Lan-Hsiang
Project Start
2004-01-01
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2010-12-31
Support Year
5
Fiscal Year
2009
Total Cost
$349,641
Indirect Cost
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
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