PHARMACOLOGIC NEUROMODULATION TARGETING NEUROINFLAMMATION AS A NOVEL THERAPEUTIC STRATEGY FOR PULMONARY HYPERTENSION AND RIGHT HEART FAILURE

Abstract

TYPE: Late Breaking Abstract TOPIC: Pulmonary Vascular Disease PURPOSE: Pulmonary hypertension (PH) is associated with aberrant sympathoexcitation leading to right ventricular failure (RVF). Neuroinflammation has been implicated in sympathoexcitation in experimental PH. Here we hypothesize that pharmacologic neuromodulation targeting TSC neuroinflammation may serve as a novel therapy for PH and RVF. METHODS: Adult male Sprague Dawley rats received either Monocrotaline (MCT, 60mg/kg, subcutaneous, n=10) and were followed for 4-weeks or Sugen (SuHx, 20mg/kg, subcutaneous, n=10) and kept in hypoxia (10% O2) for 3-weeks followed by 2-weeks of normoxia. Saline treated rats served as controls (CTRL, n=10). Next, MCT-rats received either daily intrathecal specific NOS1-inhibitor S-Methyl-L-thiocitrulline (SMTC; 0.5mg/kg, n=7) or PBS (n=7) from day 14-28. Echo and RV-catheterization were performed terminally. TSC, lung and RV RNASeq, RT-qPCR, NOS1 activity and immunolocalization, and catecholamine ELISA were performed. RESULTS: MCT and SuHx rats highlighted similar degree of PH, RVF and TSC-specific neuroinflammation and apoptosis. TSC transcriptome showed common genes and pathways linked to neuroinflammation, nitrosative stress and apoptosis. NOS1 was one of the top-most upregulated genes in TSC. NOS1-specific inhibition rescued PH, RV-hypertrophy, and RVF (all p<0.05). SMTC significantly decreased pulmonary arteriolar wall thickness, TSC NOS activity, microglia and astrocyte activation, apoptosis, plasma catecholamines and QTc prolongation (all p<0.05). This rescue was associated with reversal of RV and lung transcriptome and sympathoexcitation. CONCLUSIONS: Pharmacologic neuromodulation via intrathecal NOS1-specific inhibition rescues PH and RVF by reducing TSC neuroinflammation, apoptosis and sympathoexcitation in rats. CLINICAL IMPLICATIONS: Targeting NOS1 in TSC may serve as a novel therapeutic strategy for clinical PH and RVF. DISCLOSURE: No significant relationships. KEYWORD: Pulmonary Hypertension