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SHR Neuro Cancer Cardio Lipid Metab Microb

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.
Slack K+ channels confer protection against myocardial ischemia/reperfusion injury.
Cardiovasc Res. 2024; Doi: 10.1093/cvr/cvae155
Web of Science PubMed FullText FullText_MUG

 

Co-authors Med Uni Graz

Bischof Helmut

Burgstaller Sandra

Malli Roland

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Abstract:

AIMS: 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. METHODS: 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. CONCLUSIONS: 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.

Find related publications in this database (Keywords)

Cardiomyocyte

Cardioprotection

Ischaemia/reperfusion

K+ biosensor

KCNT1

K(Na)1.1

Myocardial infarction

Slack

Slo2.2

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