Background: Pulmonary hypertension (PH) is associated with aberrant sympathoexcitation leading to right ventricular failure (RVF), arrhythmias, and death. Microglial activation and neuroinflammation have been implicated in sympathoexcitation in experimental PH. We recently reported the first evidence of thoracic spinal cord (TSC) neuroinflammation in PH rats. Here, we hypothesize that PH is associated with increased cardiopulmonary afferent signaling leading to TSC-specific neuroinflammation and sympathoexcitation. Furthermore, inhibition of TSC neuroinflammation rescues experimental PH and RVF.
Methods: We performed transcriptomic analysis and its validation on the TSC of monocrotaline (n=8) and Sugen hypoxia (n=8) rat models of severe PH-RVF. A group of monocrotaline rats received either daily intrathecal microglial activation inhibitor minocycline (200 μg/kg per day, n=5) or PBS (n=5) from day 14 through 28. Echocardiography and right ventricle-catheterization were performed terminally. Real-time quantitative reverse transcription PCR, immunolocalization, microglia+astrocyte quantification, and terminal deoxynucleotidyl transferase dUTP nick end labeling were assessed. Plasma catecholamines were measured by ELISA. Human spinal cord autopsy samples (Control n=3; pulmonary arterial hypertension n=3) were assessed to validate preclinical findings.
Results: Increased cardiopulmonary afferent signaling was demonstrated in preclinical and clinical PH. Our findings delineated common dysregulated genes and pathways highlighting neuroinflammation and apoptosis in the remodeled TSC and highlighted increased sympathoexcitation in both rat models. Moreover, we validated significantly increased microglial and astrocytic activation and CX3CL1 expression in TSC of human pulmonary arterial hypertension. Finally, amelioration of TSC neuroinflammation by minocycline in monocrotaline rats inhibited microglial activation, decreased proinflammatory cytokines, sympathetic nervous system activation and significantly attenuated PH and RVF.
Conclusions: Targeting neuroinflammation and associated molecular pathways and genes in the TSC may yield novel therapeutic strategies for PH and RVF.
Keywords: minocycline; neuroinflammation; pulmonary hypertension; sympathoexcitation; thoracic spinal cord; transcriptome.