Vascular KATP channels protect from cardiac dysfunction and preserve cardiac metabolism during endotoxemia

Abstract

K ATP channels in the vasculature composed of Kir6.1 regulate vascular tone and may contribute to the pathogenesis of endotoxemia. We used mice with cell-specific deletion of Kir6.1 in smooth muscle (smKO) and endothelium (eKO) to investigate this question. We found that smKO mice had a significant survival disadvantage compared with their littermate controls when treated with a sub-lethal dose of lipopolysaccharide (LPS). All cohorts of mice became hypotensive following bacterial LPS administration; however, mean arterial pressure in WT mice recovered to normal levels, whereas smKO struggled to overcome LPS-induced hypotension. In vivo and ex vivo investigations revealed pronounced cardiac dysfunction in LPS-treated smKO, but not in eKO mice. Similar results were observed in a cecal slurry injection model. Metabolomic profiling of hearts revealed significantly reduced levels of metabolites involved in redox/energetics, TCA cycle, lipid/fatty acid and amino acid metabolism. Vascular smooth muscle-localised K ATP channels have a critical role in the response to systemic infection by normalising cardiac function and haemodynamics through metabolic homeostasis. Key messages • Mice lacking vascular K ATP channels are more susceptible to death from infection. • Absence of smooth muscle K ATP channels depresses cardiac function during infection. • Cardiac dysfunction is accompanied by profound changes in cellular metabolites. • Findings from this study suggest a protective role for vascular K ATP channels in response to systemic infection. Electronic supplementary material The online version of this article (10.1007/s00109-020-01946-3) contains supplementary material, which is available to authorized users.

Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases

“…Cardiac K ATP channels provide cardioprotection against ischemia/reperfusion injury; in contrast, overexpressed cardiac K ATP channels have proarrhythmic effects, which associates them with profound value for clinical applications and exploration. There are three subtypes of K ATP channels found within the cardiovascular system: two widely accepted channels, mitoK ATP and sarcolemma K ATP , and a controversial K ATP channel, plasma membrane K ATP ( Iguchi et al, 2019 ; Pertiwi et al, 2019 ; Aziz et al, 2020 ; Jiang et al, 2021 ) . Different cardiac K ATP channels play different roles in the cardiovascular system, which will be explained here.…”