Alterations of cellular bioenergetics in pulmonary artery endothelial cells

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is pathogenetically related to low levels of the vasodilator nitric oxide (NOcellular respiration ͉ nitric oxide ͉ oxygen consumption ͉ pulmonary hypertension ͉ mitochondrion I diopathic pulmonary arterial hypertension (IPAH) is a fatal disease of unknown etiology characterized by a progressive increase in pulmonary artery pressure and vascular growth (1, 2). Secondary forms of pulmonary arterial hypertension (PAH) are associated with known diseases, such as collagen vascular diseases or portal hypertension but in the absence of an identifiable etiology are classified as IPAH. Abnormalities in vasodilators, specifically nitric oxide (NO), have been implicated in the pathogenesis of pulmonary hypertension (1-5). NO is produced in the lung by NO synthases (NOS; EC 1.14.13.39) (6-8). There is conclusive evidence from animal models of pulmonary hypertension, mice genetically deficient in endothelial NOS (eNOS), and complementation studies with gene transfer of NOSs for the concept that NO is a critical determinant of pulmonary vascular tone (6, 7, 9). Furthermore, pulmonary and total body NO are lower in IPAH patients as compared with healthy controls (3,(10)(11)(12), and the decrease of NO has been linked to increased arginase II and decreased eNOS expression in IPAH pulmonary endothelial cells in vivo (10,13).In addition to effects on vascular tone, NO regulates cellular bioenergetics through effects on glycolysis, oxygen consumption by mitochondrion, and mitochondrial biogenesis (14-17). For example, eNOS-deficient mice, which have mild pulmonary hypertension under normoxia and an exaggerated pulmonary vasoconstrictive response to hypoxia (18), have reduced mitochondria content in a wide range of tissues in association with significantly lower oxygen consumption and ATP content (14-17). Mitochondria are essential to cellular energy production in all higher organisms adapted to an oxygen-containing environment, i.e., ATP produced through oxidative phosphorylation. The electrochemical gradient used by mitochondrial F 0 F 1 ATP synthase to synthesize ATP from ADP is generated by the proton pump action performed by Complexes I, III, and IV of the respiratory chain. The proton pumping is accompanied by electron shuttling, whereby Complexes I and II, along with the flavoprotein-ubiquinone oxidoreductase, transfer electrons from different sources to ubiquinone (coenzyme Q). The electrons are then transferred sequentially to Complex III, cytochrome c, Complex IV, and finally to molecular oxygen, the terminal electron acceptor. All multisubunit complexes of the respiratory chain (I-IV) are located in the mitochondrial inner membrane. Thus, mitochondria are the primary oxygen demand in the body, accounting for Ϸ90% of cellular oxygen consumption. Conversely, under limiting oxygen conditions, cells turn to glycolysis to generate energy. In endothelial cells, ATP is generated nearly equivalently by glycolysis and cellular respiration (19), accounting for a relative tolerance ...

Pulmonary 2‐Deoxy‐2‐[18F]‐Fluoro‐D‐Glucose Uptake is Low in Treated Patients with Idiopathic Pulmonary Arterial Hypertension

“…In addition, comparing the present results with data from the literature shows that the IPAH lung SUVs are comparable to those of healthy controls in the literature. 6,12 A recent report showed that in vivo pulmonary 18 FDG uptake was higher in a rat model of PAH than in control rats. 3 These in vivo data were supported by increased glucose uptake in cultured rat PASMCs and increased glucose transporter 1 expression in both rat PASMCs and pulmonary artery endothelial cells (PAECs).…”

“…In addition, two pilot studies have reported increased 18 FDG uptake in the lungs of patients with idiopathic PAH (IPAH), but no relationship between 18 FDG uptake and disease severity has been shown. 6,7 Therefore, the purpose of the present study is twofold: (1) to measure 18 FDG uptake in the lungs of IPAH patients and (2) to relate these measurements to PAH disease severity and survival.…”

Hypoxia and chronic lung disease

“…These cells have greater proliferation rate and decreased apoptosis, higher level of phosphorylated STAT3 and increased expression of its downstream prosurvival target, Mcl-1 [55]. Moreover, endothelial cells from idiopathic PAH lungs have decreased mitochondria and use preferentially the glycolytic pathway to generate energy, properties in common to cancer cells [56]. Although the involvement of HIF in this phenotype and in disease severity has not yet been formally tested, it is conceivable that vascular cells have an altered hypoxia-sensing mechanism, predisposing them to increased growth potential and even genomic instability.…”

Bone Morphogenetic Protein Receptor II Is a Novel Mediator of Endothelial Nitric-oxide Synthase Activation

“…Mutant hPAECs were isolated from patient lungs at the time of transplant as described previously (13,14). Mutant #1 has a deletion in exons 1-8 whereas mutant #2 has a deletion in exons 4 -5. bPAECs were cultured in microvascular endothelial growth medium (EGM2-MV; Lonza).…”