Novel Insights Into Molecular Pathways Induced by Glycolytic Stress in the Pathogenesis of Pulmonary Hypertension

The study identifies glycolytic stress, induced by overexpression of glucose transporter GLUT4, as a driver of the spontaneous pulmonary arterial hypertension (PAH) phenotype. This glycolytic stress is associated with a novel, previously undescribed mechanism of mitochondrial dysfunction, triggered by the activation of transcriptional repressors RBPJ and SPEN, which inhibit the expression of critical mitochondrial enzymes, PDH and SDH. The molecular pathway responsible for the disease initiation and progression is related to the overactivation of inositol monophosphatase 1 (IMPA1), which is sensitive to the upregulated G6P levels. IMPA1 is a critical regulator of de novo synthesis and recycling of myo-inositol, the main precursor to all bioactive inositols. Therefore, inhibition of IMPA1 by a selective pharmacological inhibitor effectively prevents the development of the over-proliferative state in pulmonary vascular cells, driven by inositol-dependent AKT pathway, and preserves pulmonary hemodynamics and right ventricular hypertrophy at control levels.