Slowly activating voltage-gated potassium current potentiation by ML277 is a novel cardioprotective intervention



Brennan, Sean ORCID: 0000-0002-7604-9842, Alnaimi, Abrar IM, Mcguinness, Lauren R, Abdelaziz, Muhammad IM, Mckenzie, Robert A, Draycott, Sophie, Whitmore, Jacob, Sharma, Parveen ORCID: 0000-0002-5534-2417 and Rainbow, Richard D ORCID: 0000-0002-0532-1992
(2023) Slowly activating voltage-gated potassium current potentiation by ML277 is a novel cardioprotective intervention. PNAS NEXUS, 2 (5). pgad156-.

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Abstract

Cardiovascular disease is thought to account for nearly a third of deaths worldwide, with ischemic heart disease, including acute coronary syndromes such as myocardial infarction, accounting for 1.7 million deaths per year. There is a clear need for interventions to impart cardioprotection against ischemia. Here, we show that the slowly activating voltage-gated potassium current (IKs) potentiator ML277 imparts cardioprotection against ischemia in cellular and whole-heart models by modulating the action potential duration. In three different metabolic inhibition and reperfusion models, an increased contractile recovery and cell survival was observed with ML277, indicative of protection. Finally, ML277 reduced infarct size in an ex vivo Langendorff coronary ligation model, including if only applied on reperfusion. In conclusion, potentiation of the IKs with ML277 imparted a cardioprotection that was equivalent to the protection reported previously by ischemic preconditioning. These data suggest that IKs potentiation may be therapeutically useful in acute coronary syndromes.

Item Type: Article
Uncontrolled Keywords: slowly activating voltage-gated potassium current (IKs), cardioprotection, KCNQ1 (Kv7.1)/KCNE1, ischemic protection, myocardial infarction
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Depositing User: Symplectic Admin
Date Deposited: 12 May 2023 15:46
Last Modified: 21 Sep 2023 05:40
DOI: 10.1093/pnasnexus/pgad156
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3170279