Platelet glycolytic metabolism correlates with hemodynamic severity in pulmonary arterial hypertension

Abstract

Group 1 pulmonary hypertension (PH), i.e., pulmonary arterial hypertension (PAH), is associated with a metabolic shift favoring glycolysis in cells comprising the lung vasculature as well as skeletal muscle and right heart. We sought to determine whether this metabolic switch is also detectable in circulating platelets from PAH patients. We used Seahorse Extracellular Flux to measure bioenergetics in platelets isolated from group 1 PH (PAH), group 2 PH, patients with dyspnea and normal pulmonary artery pressures, and healthy controls. We show that platelets from group 1 PH patients exhibit enhanced basal glycolysis and lower glycolytic reserve compared with platelets from healthy controls but do not differ from platelets of group 2 PH or dyspnea patients without PH. Although we were unable to identify a glycolytic phenotype unique to platelets from PAH patients, we found that platelet glycolytic metabolism correlated with hemodynamic severity only in group 1 PH patients, supporting the known link between PAH pathology and altered glycolytic metabolism and extending this association to ex vivo platelets. Pulmonary artery pressure and pulmonary vascular resistance in patients with group 1 PH were directly associated with basal platelet glycolysis and inversely associated with maximal and reserve glycolysis, suggesting that PAH progression reduces the capacity for glycolysis even while demanding an increase in glycolytic metabolism. Therefore, platelets may provide an easy-to-harvest, real-time window into the metabolic shift occurring in the lung vasculature and represent a useful surrogate for interrogating the glycolytic shift central to PAH pathology.

Platelet-Derived TGF (Transforming Growth Factor)-β1 Enhances the Aerobic Glycolysis of Pulmonary Arterial Smooth Muscle Cells by PKM2 (Pyruvate Kinase Muscle Isoform 2) Upregulation

“…Some reports 8 elucidate that aerobic glycolysis mediates PASMCs hyperproliferation and resistance to apoptosis causing pulmonary arterial remodeling. Although other studies have confirmed that platelet is activated in both patients with PAH and murine models, 13,[35][36][37][38][39] there has been little attention towards the platelet effect on PASMCs aerobic glycolysis. Previous studies have reported that the levels of TGF-β isoforms increase and the TGF-β-dependent signaling enhances in both familial PAH and IPAH (idiopathic pulmonary arterial hypertension) patients' lungs.…”

Comprehensive analysis and validation of novel immune and vascular remodeling related genes signature associated with drug interactions in pulmonary arterial hypertension

“…Hypoxia is related to inducing pulmonary vascular remodeling and the process of lipid mediators in PAH pathophysiology ( Voelkel and Tuder, 2000 ). Platelet glycolytic metabolism correlates with hemodynamic severity and aberrant lung vasculature in pulmonary arterial hypertension ( McDowell et al, 2020 ). Finally, we have verified the expression level of the 10 screened hub genes in lung tissue of rats with PAH, and the validation results are highly consistent with our analysis.…”

Platelets, extracellular vesicles and coagulation in pulmonary arterial hypertension

“…This is defined by increased basal glycolysis and reduced glycolytic reserve. 28 , 29 Interestingly, platelet bioenergetics has been correlated with haemodynamic parameters, including mean pulmonary artery pressure and pulmonary vascular resistance (PVR). 28 These quantitative and qualitative platelet abnormalities highlight the potential role of platelets in the pathobiology of PAH and the importance of further studies in this field.…”