Deletion of Kvβ2 (AKR6) Attenuates Isoproterenol Induced Cardiac Injury with Links to Solute Carrier Transporter SLC41a3 and Circadian Clock Genes
Kvβ subunits belong to the aldo-keto reductase superfamily, which plays a significant role in ion channel regulation and modulates the physiological responses. However, the role of Kvβ2 in cardiac pathophysiology was not studied, and therefore, in the present study, we hypothesized that Kvβ2 plays a...
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MDPI AG
2021-03-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/11/4/201 |
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| author | Jared Tur Kalyan C. Chapalamadagu Ravikumar Manickam Feng Cheng Srinivas M. Tipparaju |
| author_facet | Jared Tur Kalyan C. Chapalamadagu Ravikumar Manickam Feng Cheng Srinivas M. Tipparaju |
| author_sort | Jared Tur |
| collection | DOAJ |
| description | Kvβ subunits belong to the aldo-keto reductase superfamily, which plays a significant role in ion channel regulation and modulates the physiological responses. However, the role of Kvβ2 in cardiac pathophysiology was not studied, and therefore, in the present study, we hypothesized that Kvβ2 plays a significant role in cardiovascular pathophysiology by modulating the cardiac excitability and gene responses. We utilized an isoproterenol-infused mouse model to investigate the role of Kvβ2 and the cardiac function, biochemical changes, and molecular responses. The deletion of Kvβ2 attenuated the QTc (corrected QT interval) prolongation at the electrocardiographic (ECG) level after a 14-day isoproterenol infusion, whereas the QTc was significantly prolonged in the littermate wildtype group. Monophasic action potentials verified the ECG changes, suggesting that cardiac changes and responses due to isoproterenol infusion are mediated similarly at both the in vivo and ex vivo levels. Moreover, the echocardiographic function showed no further decrease in the ejection fraction in the isoproterenol-stimulated Kvβ2 knockout (KO) group, whereas the wildtype mice showed significantly decreased function. These experiments revealed that Kvβ2 plays a significant role in cardiovascular pathophysiology. Furthermore, the present study revealed SLC41a3, a major solute carrier transporter affected with a significantly decreased expression in KO vs. wildtype hearts. The electrical function showed that the decreased expression of SLC41a3 in Kvβ2 KO hearts led to decreased Mg<sup>2+</sup> responses, whereas, in the wildtype hearts, Mg<sup>2+</sup> caused action potential duration (APD) shortening. Based on the in vivo, ex vivo, and molecular evaluations, we identified that the deletion of Kvβ2 altered the cardiac pathophysiology mediated by SLC41a3 and altered the NAD (nicotinamide adenine dinucleotide)-dependent gene responses. |
| first_indexed | 2024-03-10T12:49:10Z |
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| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T12:49:10Z |
| publishDate | 2021-03-01 |
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| series | Metabolites |
| spelling | doaj.art-38ab375fbb5e45dabb208925c20c704b2023-11-21T13:11:08ZengMDPI AGMetabolites2218-19892021-03-0111420110.3390/metabo11040201Deletion of Kvβ2 (AKR6) Attenuates Isoproterenol Induced Cardiac Injury with Links to Solute Carrier Transporter SLC41a3 and Circadian Clock GenesJared Tur0Kalyan C. Chapalamadagu1Ravikumar Manickam2Feng Cheng3Srinivas M. Tipparaju4Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USADepartment of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USADepartment of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USADepartment of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USADepartment of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USAKvβ subunits belong to the aldo-keto reductase superfamily, which plays a significant role in ion channel regulation and modulates the physiological responses. However, the role of Kvβ2 in cardiac pathophysiology was not studied, and therefore, in the present study, we hypothesized that Kvβ2 plays a significant role in cardiovascular pathophysiology by modulating the cardiac excitability and gene responses. We utilized an isoproterenol-infused mouse model to investigate the role of Kvβ2 and the cardiac function, biochemical changes, and molecular responses. The deletion of Kvβ2 attenuated the QTc (corrected QT interval) prolongation at the electrocardiographic (ECG) level after a 14-day isoproterenol infusion, whereas the QTc was significantly prolonged in the littermate wildtype group. Monophasic action potentials verified the ECG changes, suggesting that cardiac changes and responses due to isoproterenol infusion are mediated similarly at both the in vivo and ex vivo levels. Moreover, the echocardiographic function showed no further decrease in the ejection fraction in the isoproterenol-stimulated Kvβ2 knockout (KO) group, whereas the wildtype mice showed significantly decreased function. These experiments revealed that Kvβ2 plays a significant role in cardiovascular pathophysiology. Furthermore, the present study revealed SLC41a3, a major solute carrier transporter affected with a significantly decreased expression in KO vs. wildtype hearts. The electrical function showed that the decreased expression of SLC41a3 in Kvβ2 KO hearts led to decreased Mg<sup>2+</sup> responses, whereas, in the wildtype hearts, Mg<sup>2+</sup> caused action potential duration (APD) shortening. Based on the in vivo, ex vivo, and molecular evaluations, we identified that the deletion of Kvβ2 altered the cardiac pathophysiology mediated by SLC41a3 and altered the NAD (nicotinamide adenine dinucleotide)-dependent gene responses.https://www.mdpi.com/2218-1989/11/4/201Kvβ subunitredoxpotassium channelheartaldo-keto reductasepyridine nucleotides |
| spellingShingle | Jared Tur Kalyan C. Chapalamadagu Ravikumar Manickam Feng Cheng Srinivas M. Tipparaju Deletion of Kvβ2 (AKR6) Attenuates Isoproterenol Induced Cardiac Injury with Links to Solute Carrier Transporter SLC41a3 and Circadian Clock Genes Metabolites Kvβ subunit redox potassium channel heart aldo-keto reductase pyridine nucleotides |
| title | Deletion of Kvβ2 (AKR6) Attenuates Isoproterenol Induced Cardiac Injury with Links to Solute Carrier Transporter SLC41a3 and Circadian Clock Genes |
| title_full | Deletion of Kvβ2 (AKR6) Attenuates Isoproterenol Induced Cardiac Injury with Links to Solute Carrier Transporter SLC41a3 and Circadian Clock Genes |
| title_fullStr | Deletion of Kvβ2 (AKR6) Attenuates Isoproterenol Induced Cardiac Injury with Links to Solute Carrier Transporter SLC41a3 and Circadian Clock Genes |
| title_full_unstemmed | Deletion of Kvβ2 (AKR6) Attenuates Isoproterenol Induced Cardiac Injury with Links to Solute Carrier Transporter SLC41a3 and Circadian Clock Genes |
| title_short | Deletion of Kvβ2 (AKR6) Attenuates Isoproterenol Induced Cardiac Injury with Links to Solute Carrier Transporter SLC41a3 and Circadian Clock Genes |
| title_sort | deletion of kvβ2 akr6 attenuates isoproterenol induced cardiac injury with links to solute carrier transporter slc41a3 and circadian clock genes |
| topic | Kvβ subunit redox potassium channel heart aldo-keto reductase pyridine nucleotides |
| url | https://www.mdpi.com/2218-1989/11/4/201 |
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