{Reference Type}: Journal Article
{Title}: Slack K+ channels confer protection against myocardial ischemia/reperfusion injury.
{Author}: Roslan A;Paulus K;Yang J;Matt L;Bischof H;Längst N;Schanz S;Luczak A;Cruz Santos M;Burgstaller S;Skrabak D;Bork NI;Malli R;Schmidtko A;Gawaz M;Nikolaev VO;Ruth P;Ehinger R;Lukowski R;
{Journal}: Cardiovasc Res
{Volume}: 0
{Issue}: 0
{Year}: 2024 Aug 5
{Factor}: 13.081
{DOI}: 10.1093/cvr/cvae155
{Abstract}: <B>OBJECTIVE: </B>Na+-activated Slack potassium (K+) channels are increasingly recognized as regulators of neuronal activity, yet little is known about their role in the cardiovascular system. Slack activity increases when intracellular Na+ concentration ([Na+]i) reaches pathophysiological levels. Elevated [Na+]i is a major determinant of the ischemia and reperfusion (I/R)-induced myocardial injury, thus we hypothesized that Slack plays a role under these conditions.<BR><B>METHODS: </B>and results: K+ currents in cardiomyocytes (CMs) obtained from wildtype (WT) but not from global Slack knockout (KO) mice were sensitive to electrical inactivation of voltage-sensitive Na+-channels. Live-cell imaging demonstrated that K+ fluxes across the sarcolemma rely on Slack, while the depolarized resting membrane potential in Slack-deficient CMs led to excessive cytosolic Ca2+ accumulation and finally to hypoxia/reoxygenation-induced cell death. Cardiac damage in an in vivo model of I/R was exacerbated in global and CM-specific conditional Slack mutants and largely insensitive to mechanical conditioning maneuvers. Finally, the protection conferred by mitochondrial ATP-dependent K+ channels required functional Slack in CMs.<BR><B>CONCLUSIONS: </B>Collectively, our study provides evidence for Slack's crucial involvement in the ion homeostasis of no or low O2-stressed CMs. Thereby, Slack activity opposes the I/R-induced fatal Ca2+-uptake to CMs supporting the cardioprotective signaling widely attributed to mitoKATP function.