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Cardiomyocyte sulfonylurea receptor 2-KATP channel mediates cardioprotection and ST segment elevation
Douglas A Stoller1, John P Fahrenbach, Karel Chalupsky
1Committee on Cellular and Molecular Physiology, University of Chicago, Chicago, IL 60637, USA.
Abstract:
Sulfonylurea receptor-containing ATP-sensitive potassium (K(ATP)) channels have been implicated in cardioprotection, but the cell type and constitution of channels responsible for this protection have not been clear. Mice deleted for the first nucleotide binding region of sulfonylurea receptor 2 (SUR2) are referred to as SUR2 null since they lack full-length SUR2 and glibenclamide-responsive K(ATP) channels in cardiac, skeletal, and smooth muscle. As previously reported, SUR2 null mice develop electrocardiographic changes of ST segment elevation that were shown to correlate with coronary artery vasospasm. Here we restored expression of the cardiomyocyte SUR2-K(ATP) channel in SUR2 null mice by generating transgenic mice with ventricular cardiomyocyte-restricted expression of SUR2A. Introduction of the cardiomyocyte SUR2A transgene into the SUR2 null background restored functional cardiac K(ATP) channels. Hearts isolated from rescued mice, referred to as MLC2A, had significantly reduced infarct size (27 ± 3% of area at risk) compared with SUR2 null mice (36 ± 3% of area at risk). Compared with SUR2 null hearts, MLC2A hearts exhibited significantly improved cardiac function during the postischemia reperfusion period primarily because of preservation of low diastolic pressures. Additionally, restoration of cardiac SUR2-K(ATP) channels significantly reduced the degree and frequency of ST segment elevation episodes in MLC2A mice. Therefore, cardioprotective mechanisms both dependent and independent of SUR2-K(ATP) channels contribute to cardiac function.
Insights
Restoring cardiomyocyte SUR2-K(ATP) channels in SUR2 null mice reduced heart infarct size and improved cardiac function. This highlights the role of these channels in cardioprotection and reducing ST segment elevation.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Ion Channel Biology
Background:
- Sulfonylurea receptor-containing ATP-sensitive potassium (K(ATP)) channels are linked to cardioprotection, but their specific cellular roles remain unclear.
- SUR2 null mice, lacking full-length SUR2, exhibit ST segment elevation and coronary artery vasospasm.
- Understanding the precise contribution of cardiomyocyte SUR2-K(ATP) channels is crucial for elucidating cardioprotective mechanisms.
Purpose of the Study:
- To investigate the role of cardiomyocyte SUR2-K(ATP) channels in cardioprotection.
- To determine if restoring SUR2A expression in cardiomyocytes of SUR2 null mice can mitigate cardiac damage and dysfunction.
- To analyze the impact of cardiomyocyte SUR2-K(ATP) channel restoration on electrocardiographic changes.
Main Methods:
- Generation of transgenic mice (MLC2A) with cardiomyocyte-restricted expression of SUR2A in a SUR2 null background.
- Assessment of infarct size and cardiac function during post-ischemia reperfusion in isolated hearts.
- Monitoring of electrocardiographic changes, specifically ST segment elevation, in the different mouse models.
Main Results:
- Restoration of functional cardiac K(ATP) channels in MLC2A mice.
- Significantly reduced infarct size in MLC2A hearts (27%) compared to SUR2 null hearts (36%).
- Improved cardiac function and preserved low diastolic pressures in MLC2A hearts during reperfusion, along with reduced ST segment elevation.
Conclusions:
- Cardiomyocyte SUR2-K(ATP) channels play a significant role in cardioprotection, reducing infarct size and improving post-ischemic function.
- Restoration of these channels mitigates ST segment elevation, suggesting a link to vasospasm.
- Both SUR2-K(ATP) channel-dependent and -independent mechanisms contribute to overall cardiac function and protection.
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