Inhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injury
Abstract BKCa channels are large-conductance calcium and voltage-activated potassium channels that are heterogeneously expressed in a wide array of cells. Activation of BKCa channels present in mitochondria of adult ventricular cardiomyocytes is implicated in cardioprotection against ischemia-reperf...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-022-00980-z |
| _version_ | 1811260845221478400 |
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| author | Shridhar Sanghvi Kalina Szteyn Devasena Ponnalagu Divya Sridharan Alexander Lam Inderjot Hansra Ankur Chaudhury Uddalak Majumdar Andrew R. Kohut Shubha Gururaja Rao Mahmood Khan Vidu Garg Harpreet Singh |
| author_facet | Shridhar Sanghvi Kalina Szteyn Devasena Ponnalagu Divya Sridharan Alexander Lam Inderjot Hansra Ankur Chaudhury Uddalak Majumdar Andrew R. Kohut Shubha Gururaja Rao Mahmood Khan Vidu Garg Harpreet Singh |
| author_sort | Shridhar Sanghvi |
| collection | DOAJ |
| description | Abstract BKCa channels are large-conductance calcium and voltage-activated potassium channels that are heterogeneously expressed in a wide array of cells. Activation of BKCa channels present in mitochondria of adult ventricular cardiomyocytes is implicated in cardioprotection against ischemia-reperfusion (IR) injury. However, the BKCa channel’s activity has never been detected in the plasma membrane of adult ventricular cardiomyocytes. In this study, we report the presence of the BKCa channel in the plasma membrane and mitochondria of neonatal murine and rodent cardiomyocytes, which protects the heart on inhibition but not activation. Furthermore, K+ currents measured in neonatal cardiomyocyte (NCM) was sensitive to iberiotoxin (IbTx), suggesting the presence of BKCa channels in the plasma membrane. Neonatal hearts subjected to IR when post-conditioned with NS1619 during reoxygenation increased the myocardial infarction whereas IbTx reduced the infarct size. In agreement, isolated NCM also presented increased apoptosis on treatment with NS1619 during hypoxia and reoxygenation, whereas IbTx reduced TUNEL-positive cells. In NCMs, activation of BKCa channels increased the intracellular reactive oxygen species post HR injury. Electrophysiological characterization of NCMs indicated that NS1619 increased the beat period, field, and action potential duration, and decreased the conduction velocity and spike amplitude. In contrast, IbTx had no impact on the electrophysiological properties of NCMs. Taken together, our data established that inhibition of plasma membrane BKCa channels in the NCM protects neonatal heart/cardiomyocytes from IR injury. Furthermore, the functional disparity observed towards the cardioprotective activity of BKCa channels in adults compared to neonatal heart could be attributed to their differential localization. |
| first_indexed | 2024-04-12T18:53:46Z |
| format | Article |
| id | doaj.art-3655928a181f44399fa45ce830c02a3a |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-12T18:53:46Z |
| publishDate | 2022-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-3655928a181f44399fa45ce830c02a3a2022-12-22T03:20:23ZengNature Publishing GroupCell Death Discovery2058-77162022-04-018111310.1038/s41420-022-00980-zInhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injuryShridhar Sanghvi0Kalina Szteyn1Devasena Ponnalagu2Divya Sridharan3Alexander Lam4Inderjot Hansra5Ankur Chaudhury6Uddalak Majumdar7Andrew R. Kohut8Shubha Gururaja Rao9Mahmood Khan10Vidu Garg11Harpreet Singh12Department of Physiology and Cell Biology, The Ohio State University Wexner Medical CenterDepartment of Physiology and Cell Biology, The Ohio State University Wexner Medical CenterDepartment of Physiology and Cell Biology, The Ohio State University Wexner Medical CenterDepartment of Emergency Medicine, Wexner Medical Center, The Ohio State UniversityDepartment of Internal Medicine, Drexel University College of MedicineDepartment of Physiology and Cell Biology, The Ohio State University Wexner Medical CenterDepartment of Internal Medicine, Drexel University College of MedicineCenter for Cardiovascular Research and The Heart Center, Nationwide Children’s HospitalDepartment of Internal Medicine, Drexel University College of MedicineDepartment of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern UniversityDepartment of Physiology and Cell Biology, The Ohio State University Wexner Medical CenterCenter for Cardiovascular Research and The Heart Center, Nationwide Children’s HospitalDepartment of Physiology and Cell Biology, The Ohio State University Wexner Medical CenterAbstract BKCa channels are large-conductance calcium and voltage-activated potassium channels that are heterogeneously expressed in a wide array of cells. Activation of BKCa channels present in mitochondria of adult ventricular cardiomyocytes is implicated in cardioprotection against ischemia-reperfusion (IR) injury. However, the BKCa channel’s activity has never been detected in the plasma membrane of adult ventricular cardiomyocytes. In this study, we report the presence of the BKCa channel in the plasma membrane and mitochondria of neonatal murine and rodent cardiomyocytes, which protects the heart on inhibition but not activation. Furthermore, K+ currents measured in neonatal cardiomyocyte (NCM) was sensitive to iberiotoxin (IbTx), suggesting the presence of BKCa channels in the plasma membrane. Neonatal hearts subjected to IR when post-conditioned with NS1619 during reoxygenation increased the myocardial infarction whereas IbTx reduced the infarct size. In agreement, isolated NCM also presented increased apoptosis on treatment with NS1619 during hypoxia and reoxygenation, whereas IbTx reduced TUNEL-positive cells. In NCMs, activation of BKCa channels increased the intracellular reactive oxygen species post HR injury. Electrophysiological characterization of NCMs indicated that NS1619 increased the beat period, field, and action potential duration, and decreased the conduction velocity and spike amplitude. In contrast, IbTx had no impact on the electrophysiological properties of NCMs. Taken together, our data established that inhibition of plasma membrane BKCa channels in the NCM protects neonatal heart/cardiomyocytes from IR injury. Furthermore, the functional disparity observed towards the cardioprotective activity of BKCa channels in adults compared to neonatal heart could be attributed to their differential localization.https://doi.org/10.1038/s41420-022-00980-z |
| spellingShingle | Shridhar Sanghvi Kalina Szteyn Devasena Ponnalagu Divya Sridharan Alexander Lam Inderjot Hansra Ankur Chaudhury Uddalak Majumdar Andrew R. Kohut Shubha Gururaja Rao Mahmood Khan Vidu Garg Harpreet Singh Inhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injury Cell Death Discovery |
| title | Inhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injury |
| title_full | Inhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injury |
| title_fullStr | Inhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injury |
| title_full_unstemmed | Inhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injury |
| title_short | Inhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injury |
| title_sort | inhibition of bkca channels protects neonatal hearts against myocardial ischemia and reperfusion injury |
| url | https://doi.org/10.1038/s41420-022-00980-z |
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