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

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2020-08, Vol.98 (8), p.1149-1160
• Main Authors: Aziz, Qadeer, Chen, Jianmin, Moyes, Amie J, Li, Yiwen, Anderson, Naomi A, Ang, Richard, Aksentijevic, Dunja, Sebastian, Sonia, Hobbs, Adrian J, Thiemermann, Christoph, Tinker, Andrew
• Format: Article
• Language: English
• Subjects: Amino acids; Biomedical and Life Sciences; Biomedicine; Blood pressure; Cardiac function; Cardiac muscle; Cecum; Clonal deletion; Disseminated infection; Endothelium; Endotoxemia; Hemodynamics; Homeostasis; Human Genetics; Hypotension; Infections; Internal Medicine; Lethal dose; Lipopolysaccharides; Metabolism; Metabolites; Metabolomics; Molecular Medicine; Original; Original Article; Potassium; Potassium channels; Potassium channels (inwardly-rectifying); Rodents; Slurries; Smooth muscle; Tricarboxylic acid cycle
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-020-01946-3

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.