Na+ Channel mRNA Regulation in Heart Failure
Study Details
Study Description
Brief Summary
Human heart failure (HF) has been associated with reduced cardiac sodium channel current and other electrical remodeling. Recently, the investigators have shown that downregulation of cardiac Na+ channels (SCN5A) can contribute to arrhythmic risk and that upregulation can mitigate that risk. Furthermore, the investigators have shown that the reduction in cardiac SCN5A mRNA abundance is reflected in circulating white blood cells (WBCs), which also express SCN5A, and that a reduction in SCN5A is highly predictive of appropriate implanted cardiac defibrillator (ICD) therapy. These data suggest that SCN5A regulation contributes to arrhythmic risk in HF. Other electrical remodeling events thought to contribute to arrhythmic risk include reductions in K+ currents, including Ito, IK1 and IKs are responsible. These current reductions have been linked to reduced transcription, translation and expression of the corresponding channel subunits, such as Kv4.3, Kir2.1, KvLQT1, and accessory proteins including minK and K+ channel interacting protein 2. That all these ion channels are downregulated may suggest a common mechanism to reduce ion channel expression. In this application, the investigators intend to explore an entirely novel mechanism by which SCN5A and other ion channel mRNA abundances are reduced in HF.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Detailed Description
Altered gene expression has been traditionally focused on transcriptional regulation. Nevertheless, recent large-scale analyses have revealed that as many as half of all changes in the amounts of mRNA in responses to cellular signals can be attributed to altered rates of mRNA decay. In preliminary data, we show that HuR, a member of a class of RNA stabilizing proteins that bind to AU-rich elements (ARE), is expressed in the heart and contributes to Na+ channel mRNA stability by binding to SCN5A transcript. Furthermore, HuR appears to be downregulated in human HF, perhaps contributing to the downregulation of ion channels and increased arrhythmic risk seen in HF. We propose that HuR is downregulated in HF, that this downregulation contributes to reduced Na+ and other currents and increased arrhythmic risk, and that upregulation of HuR will reduce ion channel downregulations and arrhythmic risk in
HF. The investigators specific aims are:
Aim 1: Determine the extent to which HuR can regulate ion currents in cardiomyocytes.
Aim 2: Determine the relative contributions of known ion channel posttranscriptional control mechanisms.
Aim 3: Determine the mechanism and extent to which HuR activity is downregulated in ischemic and nonischemic cardiomyopathy and the correlation with ion channel mRNA, protein, and current.
Aim 4: Determine the extent to which overexpression of HuR can raise ion channel mRNA, raise ion channel current, and reduce arrhythmic risk in ischemic and nonischemic cardiomyopathy.
Please be notified that only Aim 2 involves the usage of de-identified human heart samples.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| donor donor: normal heart samples from donor |
Other: no intervention is involved
|
| ICM ICM: heart samples with ischemic cardiomyopathy |
Other: no intervention is involved
|
| NICM NICM: heart samples with non-ischemic cardiomyopathy |
Other: no intervention is involved
|
Outcome Measures
Primary Outcome Measures
- ion channel expression [Baseline]
mRNA and protein levels of cardiac ion channels, cardiac ion currents
Secondary Outcome Measures
- HuR change [Baseline]
mRNA, protein, phosphorylation, cleavage products, and localization
Eligibility Criteria
Criteria
Inclusion Criteria:
- ischemic or non-ischemic cardiomyopathy Healthy Donor heart
Exclusion Criteria: N/A
- Not diagnosed with ischemic or non-ischemic cardiomyopathy
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- University of Minnesota
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Study00001184