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Published on: May 19, 2017
Vascular KATP channels protect from cardiac dysfunction and preserve cardiac metabolism during endotoxemia
Qadeer Aziz1, Jianmin Chen1, Amie J Moyes1
1Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
Insights
Mice lacking vascular ATP-sensitive potassium (KATP) channels in smooth muscle showed reduced survival and cardiac dysfunction during infection. These findings highlight the protective role of these channels in maintaining metabolic homeostasis and cardiovascular function during systemic infections.
Area of Science:
- Cardiovascular Physiology
- Vascular Biology
- Infectious Disease Pathogenesis
Background:
- ATP-sensitive potassium (KATP) channels, specifically Kir6.1, are present in the vasculature and influence vascular tone.
- These channels may play a role in the development of endotoxemia, a condition caused by bacterial toxins.
Purpose of the Study:
- To investigate the role of vascular smooth muscle-localized KATP channels in the response to systemic infection using genetically modified mice.
- To determine the impact of Kir6.1 deletion in smooth muscle and endothelial cells on survival, cardiovascular function, and cardiac metabolism during endotoxemia.
Main Methods:
- Utilized mice with cell-specific deletion of Kir6.1 in smooth muscle (smKO) and endothelium (eKO).
- Administered lipopolysaccharide (LPS) to induce endotoxemia and assessed survival, mean arterial pressure, and cardiac function (in vivo and ex vivo).
- Employed metabolomic profiling of heart tissue to analyze metabolic changes.
Main Results:
- smKO mice exhibited significantly reduced survival rates and prolonged hypotension following LPS administration compared to controls.
- LPS-treated smKO mice displayed pronounced cardiac dysfunction, which was not observed in eKO mice.
- Metabolomic analysis of hearts from LPS-treated smKO mice revealed decreased levels of metabolites crucial for redox/energetics, TCA cycle, and lipid/amino acid metabolism.
Conclusions:
- Vascular smooth muscle KATP channels are critical for maintaining cardiac function and hemodynamic stability during systemic infection.
- These channels contribute to metabolic homeostasis, suggesting a protective role against infection-induced cardiovascular compromise.
- Targeting vascular KATP channels may offer therapeutic potential in managing sepsis and related conditions.
Abstract:
KATP 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 KATP 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 KATP channels are more susceptible to death from infection. • Absence of smooth muscle KATP 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 KATP channels in response to systemic infection.
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