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

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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. © 2011 American Physiological Society. Compr Physiol 1:357‐372, 2011.

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Figure 1. Figure 1.

Ki‐67 in idiopathic pulmonary arterial hypertension (IPAH) lung. IPAH plexiform lesion shows intense immunoreactivity of proliferative endothelial cells for nuclear Ki‐67 antigen (arrows) in low power view (B) and high power view (C). H&E staining of the plexiform lesion (A). (Original magnification: A and B: ×200; C: ×400)

Figure 2. Figure 2.

Signal transduction pathway for STAT3. IL‐6, Epo, or growth factors bind their receptors on endothelial cells and induce a tyrosine (Tyr) phosphorylation cascade, which involves activation of receptor‐associated Janus kinase family tyrosine kinases (Jak/Tyk) by cross‐phosphorylation. STAT3 phosphorylation, homodimerization and/or heterodimerization (with STAT1) and translocation to the nucleus, is followed by binding to DNA elements to activate transcription of genes that promote angiogenesis and cell survival, such as vascular endothelial growth factor (VEGF) and HIF‐1α. Serine (Ser) phosphorylation of STAT 3 appears to be required for its action in mitochondria. Bone morphogenetic proteins (BMPs) bind to bone morphogenetic protein receptor type II (BMPRII) and induce growth arrest through intracellular signaling pathways of the Smad proteins, which act in part through interaction with, and inactivation of, STAT3.

EPO, erythropoietin; GAS, γ‐activated site; SIE, cis‐inducible element. © Copyright 2009 by CCF
Figure 3. Figure 3.

Positron emission tomographic (PET)/computed tomographic (CT) image, glycolytic rate in vitro, and glucose metabolic activities in vivo. (A and B) CT image of the lung of idiopathic pulmonary arterial hypertension (IPAH) (A) and healthy control subject (B). (C and D) PET image of the lung of IPAH (C) and healthy control subjects (D). (E) Glycolytic rate from IPAH endothelial cells (n = 5) was higher than that of healthy controls (n = 3) (*P < 0.01). (F) Glucose metabolic activities in the lung of IPAH patients were higher than those of healthy controls (*P < 0.01): 4 IPAH patients (subjects 4‐7) vs. 3 healthy controls (subjects 1‐3). To account for variations in lung tissue density and [18F] fluoro‐deoxy‐d‐glucose distribution between subjects, standardized uptake value (SUV) of each region of the lung was normalized for lung tissue fraction [LTF, determined from lung CT Hounsfield units (HU)] and HU of liver using the formula: SUVnormalized = SUV of each region of the lung/LTF lung of same region/mean HU of liver .

Figure 4. Figure 4.

Mitochondria oxidative phosphorylation related to NO production, MnSOD activity, and glycolysis. Complexes I and II receive electrons (depicted with an e) from different sources and transfer them to ubiquinone (coenzyme Q, CoQ). The electrons are then transferred sequentially to complex III, cytochrome c (Cyt C), complex IV, and finally to molecular oxygen, the terminal electron acceptor. All multisubunit complexes of the respiratory chain are located in the mitochondrial inner membrane. The proton (depicted by H+) pumping is performed by complexes I, III, and IV and generates an electrochemical gradient that is used by complex V to synthesize adenosine triphosphate (ATP). NO binds to several targets within the mitochondrial respiratory chain (e.g., complexes I, II, and IV) and inhibits their function. Superoxide (O2•−), generated from mitochondrial complexes I and III, is converted to hydrogen peroxide (H2O2) by manganese superoxide dismutase (MnSOD). Glucose is converted to pyruvate and lactate via glycolysis. Under aerobic conditions, pyruvate in most cells is further metabolized via the tricarboxylic acid (TCA) cycle. Under anaerobic conditions and in erythrocytes under aerobic conditions, pyruvate is converted to lactate, which is transported out of the cell into the circulation. Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase and thereby activates pyruvate dehydrogenase with an attendant increase in intramitochondrial acetyl coenzyme A (acetyl CoA). This drives TCA cycle and increases availability of electron donors for complexes I and II within the mitochondria.

ADP, adenosine diphosphate. © Copyright 2009 by CCF
Figure 5. Figure 5.

Ultrastructure of pulmonary artery endothelial cells (PAEC) from idiopathic pulmonary arterial hypertension (IPAH) patient and healthy control. (A) Ultrastructure of PAEC in three‐dimensional Matrigel in vitro. Healthy control PAEC with junctions and spaces between plasma membranes of two adjacent cells. Mitochondria (M) are close to caveolae (arrowheads) in control PAEC (scale bar: 250 nm). (B and C) Electron microscopy images reveal decreased mitochondrial numbers in IPAH endothelial cells compared to control. Ultrastructure detail of pulmonary artery endothelial cells from IPAH (C) and healthy control subjects (B) (scale bar: 1 μm). ER, endoplasmic reticulum; M, mitochondria; N, nucleus.

Figure 6. Figure 6.

Pathways in NO metabolism. NOS converts l‐arginine to NO and citrulline. ADMA, asymmetric dimethylarginine; BH4, tetrahydrobiopterin; cGMP, guanosine 3′,5′‐cyclic monophosphate; GSH, reduced glutathione; GSNO, S‐nitrosoglutathione; L‐Arg, l‐arginine; L‐Cit, l‐citrulline; MMA, monomethyl‐l‐arginine; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOS, nitric oxide synthases; NO2, nitrite; NO3, nitrate; O2, Orn, ornithine superoxide; OONO, peroxynitrite; SOD, superoxide dismutase.

Figure 7. Figure 7.

Endothelial nitric oxide synthase (eNOS) interactions with proteins in membrane‐bound organelles affects activation and function. Cav‐1 (caveolin‐1) is the principal component of caveolae but is also found in the outer mitochondrial membrane. Cav‐1 and eNOS colocalize at caveolae. Hsp90 interacts with and activates eNOS. eNOS is anchored to mitochondria by a pentabasic amino acid sequence (RRKRK). Agonist‐receptor binding triggers kinase cascades to phosphorylate eNOS..

© Copyright 2009 by CCF
Figure 8. Figure 8.

Endothelial nitric oxide synthase (eNOS) and phosphorylated STAT3 (pSTAT3) staining in plexiform lesion from lung of IPAH patient. IPAH vascular plexiform lesion has strong positive eNOS immunoreactivity in endothelial cells (A, arrows). Strong positive immunoreactivity of pSTAT3 is also present in endothelium in plexiform lesions (C, arrows). Immunohistochemical staining for CD31 in the laminar lining cells of the vessels confirms endothelial phenotype of cells (B and D). (Original magnification: ×200)

Figure 9. Figure 9.

Hypoxia‐inducible factor (HIF) regulation by hypoxia, STAT3, NO, and ROS. Under normoxia, prolyl hydroxylases (PHD)‐containing proteins hydroxylate HIF‐1α, which mediates von Hippel‐Lindau tumor suppressor (pVHL) binding, and HIF ubiquitination and proteasomal degradation. Under hypoxia, HIF‐1α stabilizes, dimerizes with HIF‐1β, and interacts with hypoxia‐responsive elements (HRE) leading to expression of genes, which are active in conversion to anaerobic metabolism and increasing oxygen delivery to tissues. Under normoxic conditions, HIF‐1α is stabilized by reactive oxygen species (ROS), knockdown of manganese superoxide dismutase (MnSOD), or high levels of NO, while hypoxia, MnSOD overexpression, or low levels of NO destabilize HIF‐1α. Activation of signal transducer and activator of transcription (STAT)3 increases HIF‐1α mRNA expression and protein stability. ET‐1, endothelin‐1; eNOS, endothelial NOS; Epo; erythropoietin; SDF, stromal cell–derived factor.



Figure 1.

Ki‐67 in idiopathic pulmonary arterial hypertension (IPAH) lung. IPAH plexiform lesion shows intense immunoreactivity of proliferative endothelial cells for nuclear Ki‐67 antigen (arrows) in low power view (B) and high power view (C). H&E staining of the plexiform lesion (A). (Original magnification: A and B: ×200; C: ×400)



Figure 2.

Signal transduction pathway for STAT3. IL‐6, Epo, or growth factors bind their receptors on endothelial cells and induce a tyrosine (Tyr) phosphorylation cascade, which involves activation of receptor‐associated Janus kinase family tyrosine kinases (Jak/Tyk) by cross‐phosphorylation. STAT3 phosphorylation, homodimerization and/or heterodimerization (with STAT1) and translocation to the nucleus, is followed by binding to DNA elements to activate transcription of genes that promote angiogenesis and cell survival, such as vascular endothelial growth factor (VEGF) and HIF‐1α. Serine (Ser) phosphorylation of STAT 3 appears to be required for its action in mitochondria. Bone morphogenetic proteins (BMPs) bind to bone morphogenetic protein receptor type II (BMPRII) and induce growth arrest through intracellular signaling pathways of the Smad proteins, which act in part through interaction with, and inactivation of, STAT3.

EPO, erythropoietin; GAS, γ‐activated site; SIE, cis‐inducible element. © Copyright 2009 by CCF


Figure 3.

Positron emission tomographic (PET)/computed tomographic (CT) image, glycolytic rate in vitro, and glucose metabolic activities in vivo. (A and B) CT image of the lung of idiopathic pulmonary arterial hypertension (IPAH) (A) and healthy control subject (B). (C and D) PET image of the lung of IPAH (C) and healthy control subjects (D). (E) Glycolytic rate from IPAH endothelial cells (n = 5) was higher than that of healthy controls (n = 3) (*P < 0.01). (F) Glucose metabolic activities in the lung of IPAH patients were higher than those of healthy controls (*P < 0.01): 4 IPAH patients (subjects 4‐7) vs. 3 healthy controls (subjects 1‐3). To account for variations in lung tissue density and [18F] fluoro‐deoxy‐d‐glucose distribution between subjects, standardized uptake value (SUV) of each region of the lung was normalized for lung tissue fraction [LTF, determined from lung CT Hounsfield units (HU)] and HU of liver using the formula: SUVnormalized = SUV of each region of the lung/LTF lung of same region/mean HU of liver .



Figure 4.

Mitochondria oxidative phosphorylation related to NO production, MnSOD activity, and glycolysis. Complexes I and II receive electrons (depicted with an e) from different sources and transfer them to ubiquinone (coenzyme Q, CoQ). The electrons are then transferred sequentially to complex III, cytochrome c (Cyt C), complex IV, and finally to molecular oxygen, the terminal electron acceptor. All multisubunit complexes of the respiratory chain are located in the mitochondrial inner membrane. The proton (depicted by H+) pumping is performed by complexes I, III, and IV and generates an electrochemical gradient that is used by complex V to synthesize adenosine triphosphate (ATP). NO binds to several targets within the mitochondrial respiratory chain (e.g., complexes I, II, and IV) and inhibits their function. Superoxide (O2•−), generated from mitochondrial complexes I and III, is converted to hydrogen peroxide (H2O2) by manganese superoxide dismutase (MnSOD). Glucose is converted to pyruvate and lactate via glycolysis. Under aerobic conditions, pyruvate in most cells is further metabolized via the tricarboxylic acid (TCA) cycle. Under anaerobic conditions and in erythrocytes under aerobic conditions, pyruvate is converted to lactate, which is transported out of the cell into the circulation. Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase and thereby activates pyruvate dehydrogenase with an attendant increase in intramitochondrial acetyl coenzyme A (acetyl CoA). This drives TCA cycle and increases availability of electron donors for complexes I and II within the mitochondria.

ADP, adenosine diphosphate. © Copyright 2009 by CCF


Figure 5.

Ultrastructure of pulmonary artery endothelial cells (PAEC) from idiopathic pulmonary arterial hypertension (IPAH) patient and healthy control. (A) Ultrastructure of PAEC in three‐dimensional Matrigel in vitro. Healthy control PAEC with junctions and spaces between plasma membranes of two adjacent cells. Mitochondria (M) are close to caveolae (arrowheads) in control PAEC (scale bar: 250 nm). (B and C) Electron microscopy images reveal decreased mitochondrial numbers in IPAH endothelial cells compared to control. Ultrastructure detail of pulmonary artery endothelial cells from IPAH (C) and healthy control subjects (B) (scale bar: 1 μm). ER, endoplasmic reticulum; M, mitochondria; N, nucleus.



Figure 6.

Pathways in NO metabolism. NOS converts l‐arginine to NO and citrulline. ADMA, asymmetric dimethylarginine; BH4, tetrahydrobiopterin; cGMP, guanosine 3′,5′‐cyclic monophosphate; GSH, reduced glutathione; GSNO, S‐nitrosoglutathione; L‐Arg, l‐arginine; L‐Cit, l‐citrulline; MMA, monomethyl‐l‐arginine; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOS, nitric oxide synthases; NO2, nitrite; NO3, nitrate; O2, Orn, ornithine superoxide; OONO, peroxynitrite; SOD, superoxide dismutase.



Figure 7.

Endothelial nitric oxide synthase (eNOS) interactions with proteins in membrane‐bound organelles affects activation and function. Cav‐1 (caveolin‐1) is the principal component of caveolae but is also found in the outer mitochondrial membrane. Cav‐1 and eNOS colocalize at caveolae. Hsp90 interacts with and activates eNOS. eNOS is anchored to mitochondria by a pentabasic amino acid sequence (RRKRK). Agonist‐receptor binding triggers kinase cascades to phosphorylate eNOS..

© Copyright 2009 by CCF


Figure 8.

Endothelial nitric oxide synthase (eNOS) and phosphorylated STAT3 (pSTAT3) staining in plexiform lesion from lung of IPAH patient. IPAH vascular plexiform lesion has strong positive eNOS immunoreactivity in endothelial cells (A, arrows). Strong positive immunoreactivity of pSTAT3 is also present in endothelium in plexiform lesions (C, arrows). Immunohistochemical staining for CD31 in the laminar lining cells of the vessels confirms endothelial phenotype of cells (B and D). (Original magnification: ×200)



Figure 9.

Hypoxia‐inducible factor (HIF) regulation by hypoxia, STAT3, NO, and ROS. Under normoxia, prolyl hydroxylases (PHD)‐containing proteins hydroxylate HIF‐1α, which mediates von Hippel‐Lindau tumor suppressor (pVHL) binding, and HIF ubiquitination and proteasomal degradation. Under hypoxia, HIF‐1α stabilizes, dimerizes with HIF‐1β, and interacts with hypoxia‐responsive elements (HRE) leading to expression of genes, which are active in conversion to anaerobic metabolism and increasing oxygen delivery to tissues. Under normoxic conditions, HIF‐1α is stabilized by reactive oxygen species (ROS), knockdown of manganese superoxide dismutase (MnSOD), or high levels of NO, while hypoxia, MnSOD overexpression, or low levels of NO destabilize HIF‐1α. Activation of signal transducer and activator of transcription (STAT)3 increases HIF‐1α mRNA expression and protein stability. ET‐1, endothelin‐1; eNOS, endothelial NOS; Epo; erythropoietin; SDF, stromal cell–derived factor.

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Weiling Xu, Serpil C. Erzurum. Endothelial Cell Energy Metabolism, Proliferation, and Apoptosis in Pulmonary Hypertension. Compr Physiol 2010, 1: 357-372. doi: 10.1002/cphy.c090005