Activation of Spinal Astrocyte α2A Adrenoceptors Protects Against Sepsis-Induced Heart Injury Through Inhibition of GABAergic Neuronal Necroptosis.

Abstract

The peripheral immune system contributes to the development of sepsis-induced cardiomyopathy. However, the underlying mechanisms linking central immune cells and neurons to sepsis-induced cardiomyopathy remain to be clarified. Here, acute sepsis is induced by cecal ligation puncture (CLP), and pharmacological and RNAi interventions are administered to the thoracic spinal cord via intrathecal injection. Echocardiography and histology confirm reduced cardiac function following CLP. Sepsis-induced spinal cord changes involved neuronal activation and loss with decreased gamma-aminobutyric acid (GABA) levels. Necroptosis effector genes are markedly upregulated with increased RIPK1, RIPK3, and MLKL co-expression evident in spinal GABAergic neurons, while administration of the necroptosis inhibitor Necrostatin-1 substantially preserves neurons and reverses sepsis-associated cardiac functional changes. Sepsis triggers increased C3, IL-6 and TNF-α in spinal astrocytes, while administration of the α2A-adrenergic receptor (α2-AR) agonist dexmedetomidine blocked inflammatory factor production, neuronal damage, and cardiac dysfunction. These findings suggest that sepsis-induced cardiomyopathy arises from a neuroimmune interplay involving spinal astrocyte activation, GABAergic neuronal necroptosis, and cardiac damage driven by sympathetic hyperstimulation.