Impact of Administration Time and Kv7 Subchannels on the Cardioprotective Efficacy of Kv7 Channel Inhibition
Jan Hansen,1,2,* Jacob Johnsen,1,2,* Jan Møller Nielsen,1,2 Charlotte Brandt Sørensen,1,2 Casper Carlsen Elkjær,1,2 Nichlas Riise Jespersen,1,2 Hans Erik Bøtker1,2 1Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinic...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2020-07-01
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| Series: | Drug Design, Development and Therapy |
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| Online Access: | https://www.dovepress.com/impact-of-administration-time-and-kv7-subchannels-on-the-cardioprotect-peer-reviewed-article-DDDT |
| _version_ | 1811331354265124864 |
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| author | Hansen J Johnsen J Nielsen JM Sørensen CB Elkjær CC Jespersen NR Bøtker HE |
| author_facet | Hansen J Johnsen J Nielsen JM Sørensen CB Elkjær CC Jespersen NR Bøtker HE |
| author_sort | Hansen J |
| collection | DOAJ |
| description | Jan Hansen,1,2,* Jacob Johnsen,1,2,* Jan Møller Nielsen,1,2 Charlotte Brandt Sørensen,1,2 Casper Carlsen Elkjær,1,2 Nichlas Riise Jespersen,1,2 Hans Erik Bøtker1,2 1Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark*These authors contributed equally to this workCorrespondence: Jacob JohnsenDepartment of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N 8200, DenmarkTel +45 2674 3580Email jacob.johnsen@clin.au.dkPurpose: The mechanism of cardioprotection by Kv7.1– 5 (KCNQ1-5) channels inhibition by XE991 is unclear. We examined the impact of administration time on the cardioprotective efficacy of XE991, the involvement of key pro-survival kinases, and the importance of the Kv7 subchannels.Methods: Isolated perfused rat hearts were divided into five groups: 1) vehicle, 2) pre-, 3) post- or 4) pre- and post-ischemic administration of XE991 or 5) chromanol 293B (Kv7.1 inhibitor) followed by infarct size quantification. HL-1 cells undergoing simulated ischemia/reperfusion were exposed to either a) vehicle, b) pre-, c) per-, d) post-ischemic administration of XE991 or pre-, per- and post-ischemic administration of e) XE991, f) Chromanol 293B or g) HMR1556 (Kv7.1 inhibitor). HL-1 cell injury was evaluated by propidium iodide/Hoechst staining. Pro-survival kinase activation of Akt, Erk and STAT3 in XE991-mediated HL-1 cell protection was evaluated using phosphokinase inhibitors. Kv7 subtype expression was examined by RT-PCR and qPCR.Results: XE991, but not Chromanol 293B, reduced infarct size and improved hemodynamic recovery in all isolated heart groups. XE991 protected HL-1 cells when administered during simulated ischemia. Minor activation of the survival kinases was observed in cells exposed to XE991 but pharmacological inhibition of kinase activation did not reduce XE991-mediated protection. Kv7 subchannels 1– 5 were all present in rat hearts but predominately Kv7.1 and Kv7.4 were present in HL-1 cells and selective Kv7.1 did not reduce ischemia/reperfusion injury.Conclusion: The cardioprotective efficacy of XE991 seems to depend on its presence during ischemia and early reperfusion and do not rely on RISK (p-Akt and p-Erk) and SAFE (p-STAT3) pathway activation. The protective effect of XE991 seems mainly mediated through the Kv7.4 subchannel.Keywords: cardioprotection, Kv7 channels, myocardial ischemia reperfusion injury, myocardial infarction |
| first_indexed | 2024-04-13T16:19:00Z |
| format | Article |
| id | doaj.art-8773b1357c8c4596a8341b3cd3093183 |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-04-13T16:19:00Z |
| publishDate | 2020-07-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-8773b1357c8c4596a8341b3cd30931832022-12-22T02:39:59ZengDove Medical PressDrug Design, Development and Therapy1177-88812020-07-01Volume 142549256055003Impact of Administration Time and Kv7 Subchannels on the Cardioprotective Efficacy of Kv7 Channel InhibitionHansen JJohnsen JNielsen JMSørensen CBElkjær CCJespersen NRBøtker HEJan Hansen,1,2,* Jacob Johnsen,1,2,* Jan Møller Nielsen,1,2 Charlotte Brandt Sørensen,1,2 Casper Carlsen Elkjær,1,2 Nichlas Riise Jespersen,1,2 Hans Erik Bøtker1,2 1Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark*These authors contributed equally to this workCorrespondence: Jacob JohnsenDepartment of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N 8200, DenmarkTel +45 2674 3580Email jacob.johnsen@clin.au.dkPurpose: The mechanism of cardioprotection by Kv7.1– 5 (KCNQ1-5) channels inhibition by XE991 is unclear. We examined the impact of administration time on the cardioprotective efficacy of XE991, the involvement of key pro-survival kinases, and the importance of the Kv7 subchannels.Methods: Isolated perfused rat hearts were divided into five groups: 1) vehicle, 2) pre-, 3) post- or 4) pre- and post-ischemic administration of XE991 or 5) chromanol 293B (Kv7.1 inhibitor) followed by infarct size quantification. HL-1 cells undergoing simulated ischemia/reperfusion were exposed to either a) vehicle, b) pre-, c) per-, d) post-ischemic administration of XE991 or pre-, per- and post-ischemic administration of e) XE991, f) Chromanol 293B or g) HMR1556 (Kv7.1 inhibitor). HL-1 cell injury was evaluated by propidium iodide/Hoechst staining. Pro-survival kinase activation of Akt, Erk and STAT3 in XE991-mediated HL-1 cell protection was evaluated using phosphokinase inhibitors. Kv7 subtype expression was examined by RT-PCR and qPCR.Results: XE991, but not Chromanol 293B, reduced infarct size and improved hemodynamic recovery in all isolated heart groups. XE991 protected HL-1 cells when administered during simulated ischemia. Minor activation of the survival kinases was observed in cells exposed to XE991 but pharmacological inhibition of kinase activation did not reduce XE991-mediated protection. Kv7 subchannels 1– 5 were all present in rat hearts but predominately Kv7.1 and Kv7.4 were present in HL-1 cells and selective Kv7.1 did not reduce ischemia/reperfusion injury.Conclusion: The cardioprotective efficacy of XE991 seems to depend on its presence during ischemia and early reperfusion and do not rely on RISK (p-Akt and p-Erk) and SAFE (p-STAT3) pathway activation. The protective effect of XE991 seems mainly mediated through the Kv7.4 subchannel.Keywords: cardioprotection, Kv7 channels, myocardial ischemia reperfusion injury, myocardial infarctionhttps://www.dovepress.com/impact-of-administration-time-and-kv7-subchannels-on-the-cardioprotect-peer-reviewed-article-DDDTcardioprotectionkv7 channelsmyocardial ischemia reperfusion injurymyocardial infarction. |
| spellingShingle | Hansen J Johnsen J Nielsen JM Sørensen CB Elkjær CC Jespersen NR Bøtker HE Impact of Administration Time and Kv7 Subchannels on the Cardioprotective Efficacy of Kv7 Channel Inhibition Drug Design, Development and Therapy cardioprotection kv7 channels myocardial ischemia reperfusion injury myocardial infarction. |
| title | Impact of Administration Time and Kv7 Subchannels on the Cardioprotective Efficacy of Kv7 Channel Inhibition |
| title_full | Impact of Administration Time and Kv7 Subchannels on the Cardioprotective Efficacy of Kv7 Channel Inhibition |
| title_fullStr | Impact of Administration Time and Kv7 Subchannels on the Cardioprotective Efficacy of Kv7 Channel Inhibition |
| title_full_unstemmed | Impact of Administration Time and Kv7 Subchannels on the Cardioprotective Efficacy of Kv7 Channel Inhibition |
| title_short | Impact of Administration Time and Kv7 Subchannels on the Cardioprotective Efficacy of Kv7 Channel Inhibition |
| title_sort | impact of administration time and kv7 subchannels on the cardioprotective efficacy of kv7 channel inhibition |
| topic | cardioprotection kv7 channels myocardial ischemia reperfusion injury myocardial infarction. |
| url | https://www.dovepress.com/impact-of-administration-time-and-kv7-subchannels-on-the-cardioprotect-peer-reviewed-article-DDDT |
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