Endothelial Cell Energy Metabolism, Proliferation, and Apoptosis in Pulmonary Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by impaired regulation of pulmonary hemodynamics and excessive growth and dysfunction of the endothelial cells that line the arteries in PAH lungs. Establishment of methods for culture of pulmonary artery endothelial cells from PAH lungs has provided the groundwork for mechanistic translational studies that confirm and extend findings from model systems and spontaneous pulmonary hypertension in animals. Endothelial cell hyperproliferation, survival, and alterations of biochemical-metabolic pathways are the unifying endothelial pathobiology of the disease. The hyperproliferative and apoptosis-resistant phenotype of PAH endothelial cells is dependent upon the activation of signal transducer and activator of transcription (STAT) 3, a fundamental regulator of cell survival and angiogenesis. Animal models of PAH, patients with PAH, and human PAH endothelial cells produce low nitric oxide (NO). In association with the low level of NO, endothelial cells have reduced mitochondrial numbers and cellular respiration, which is associated with more than a threefold increase in glycolysis for energy production. The shift to glycolysis is related to low levels of NO and likely to the pathologic expression of the prosurvival and proangiogenic signal transducer, hypoxia-inducible factor (HIF)-1, and the reduced mitochondrial antioxidant manganese superoxide dismutase (MnSOD). In this article, we review the phenotypic changes of the endothelium in PAH and the biochemical mechanisms accounting for the proliferative, glycolytic, and strongly proangiogenic phenotype of these dysfunctional cells, which consequently foster the panvascular progressive pulmonary remodeling in PAH.

Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?

“…This model is supported by evidence showing that siRNA knockdown of S1P 2 expression or S1P 2 antagonism with JTE-013 (which is also a competitive antagonist of S1P 4 [19]) ablated the S1P-stimulated proliferation of human PASMC [17]. This report suggested that S1P/S1P 2 uses ERK-1/2 and STAT3 signaling to promote human PASMC proliferation [17], and which is significant as STAT3 activation has been shown to be involved in pro-survival and proliferative pulmonary vascular phenotypes associated with human PAH [3,20,21]. Finally, the S1P 2/4 antagonist, JTE-013 (8 mg/kg body weight, i/p) prevented and reversed pulmonary hypertension in the hypoxic mouse model [17], thereby confirming that S1P 2 is involved in S1P-stimulated vascular remodeling in this model.…”

Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension

“…A disorder of proliferation and migration has been observed in human plexiform lesions (22), and more recent studies of hyperproliferative PAECs in PH have described an accompanying migratory phenotype (38). Such disordered migration may contribute to abnormal angiogenesis in PH -which in some cases has been linked to a proangiogenic and pathogenic remodeling of the pulmonary arteriole (39) and in other cases has been linked to a deficiency of angiogenesis (39) and a pruning of the entire pulmonary vascular tree. Consequently, our work places vessel stiffness, the YAP/TAZ-GLS1 axis, and gluta- , decreased glutamine/glutamate ratio (C), and increased aspartate (D) in an independent HIV-PAH patient cohort (n = 9) as compared with HIV-infected patients alone (n = 7).…”

Endothelial Uncoupling Protein 2 Regulates Mitophagy and Pulmonary Hypertension During Intermittent Hypoxia

“…X. Xu and S. Erzurum introduced the concept of increased glycolysis in the EC of PAH patients, potentially due to decreased mitochondrial function and increased ROS production (56). The historical work of Warburg (57), showing a predominance of glycolysis over respiration in tumors, was expanded by R. Tuder into the pathogenesis of PH (3).…”