Lipopolysaccharide-induced sepsis impairs M2R-GIRK signaling in the mouse sinoatrial node.
Niroj ShresthaKlaus Zorn-PaulyPietro MesircaChintan N KoyaniGerald WölkartValentina Di BiaseEleonora TorrePetra LangAstrid GorischekWolfgang SchreibmayerRobert ArnoldHeinrich MaechlerBernd MayerDirk von LewinskiAngelo Giovanni TorrenteMatteo E MangoniBrigitte PelzmannSusanne ScheruebelPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
Sepsis has emerged as a global health burden associated with multiple organ dysfunction and 20% mortality rate in patients. Numerous clinical studies over the past two decades have correlated the disease severity and mortality in septic patients with impaired heart rate variability (HRV), as a consequence of impaired chronotropic response of sinoatrial node (SAN) pacemaker activity to vagal/parasympathetic stimulation. However, the molecular mechanism(s) downstream to parasympathetic inputs have not been investigated yet in sepsis, particularly in the SAN. Based on electrocardiography, fluorescence Ca 2+ imaging, electrophysiology, and protein assays from organ to subcellular level, we report that impaired muscarinic receptor subtype 2-G protein-activated inwardly-rectifying potassium channel (M2R-GIRK) signaling in a lipopolysaccharide-induced proxy septic mouse model plays a critical role in SAN pacemaking and HRV. The parasympathetic responses to a muscarinic agonist, namely I KACh activation in SAN cells, reduction in Ca 2+ mobilization of SAN tissues, lowering of heart rate and increase in HRV, were profoundly attenuated upon lipopolysaccharide-induced sepsis. These functional alterations manifested as a direct consequence of reduced expression of key ion-channel components (GIRK1, GIRK4, and M2R) in the mouse SAN tissues and cells, which was further evident in the human right atrial appendages of septic patients and likely not mediated by the common proinflammatory cytokines elevated in sepsis.
Keyphrases
- lipopolysaccharide induced
- heart rate variability
- heart rate
- acute kidney injury
- inflammatory response
- intensive care unit
- septic shock
- end stage renal disease
- ejection fraction
- newly diagnosed
- induced apoptosis
- mouse model
- blood pressure
- gene expression
- endothelial cells
- cell cycle arrest
- prognostic factors
- oxidative stress
- public health
- peritoneal dialysis
- poor prognosis
- high resolution
- cell death
- atrial fibrillation
- small molecule
- quantum dots
- pulmonary embolism
- mass spectrometry
- left ventricular
- amino acid
- fluorescence imaging