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Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension

WEILING XU^*,,, F. TAKAO KANEKO^,, SHUO ZHENG^,, SUZY A. A. COMHAIR^*,,, ALLISON J. JANOCHA^*,,, TANNISHIA GOGGANS^*,,, FREDERIK B. J. M. THUNNISSEN^¶, CAROL FARVER, STANLEY L. HAZEN^||, CONSTANCE JENNINGS, RAED A. DWEIK^*,, ALEJANDRO C. ARROLIGA and SERPIL C. ERZURUM^*,,,1

Departments of
^* Pathobiology,
Pulmonary and Critical Care Medicine,
Cancer Biology,
Pathology and
^|| Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA; and
^¶ Department of Pathology, Canisius Wihelmina Ziekenhuis, Nijmegen, The Netherlands

¹Correspondence: Cleveland Clinic Foundation, Lerner Research Institute, 9500 Euclid Ave., NB40, Cleveland, Ohio 44195, USA. E-mail: erzurus{at}ccf.org

SPECIFIC AIMS

Based on its critical role in mediating vasodilation, a decrease of nitric oxide (NO) has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH), a rare disease characterized by impaired regulation of pulmonary hemodynamics and vascular growth. Although NO levels are lower in PAH lungs than healthy controls, whether a decrease of NO is due to decreased expression of NO synthase (NOS) proteins has been controversial. Our aim was to determine the mechanisms for the low NO in pulmonary hypertension. We evaluated expression of NOS and factors regulating NOS activity (i.e., substrate arginine, arginase expression and activity, and endogenous inhibitors of NOS in patients with PAH and healthy controls).

PRINCIPAL FINDINGS

1. Clinical characteristics
Nineteen healthy controls and 18 PAH World Health Organization class 1 individuals, 16 of whom were diagnosed with primary pulmonary hypertension (PPH; PAH subclass 1.1), participated in the study. Clinical characteristics of PAH patients were similar to controls. Pulmonary hypertension was diagnosed in PAH patients by right heart catheterization.

2. NOS expression in PAH is similar to controls, but arginine levels are inversely related to pulmonary artery pressures
PAH and healthy control airway epithelium had similar levels of NOS II expression by Western analyses. Positive immunoreactivity for NOS III was seen in the endothelium of arteries, arterioles, veins, and venules and was similar in intensity and distribution in healthy controls and PPH lungs.

Quantitation of arginine, substrate for synthesis of NO, by HPLC revealed that lysates of airway epithelial cells from PAH lungs contain a wide range of arginine levels not significantly different from healthy controls. Arginine levels were inversely correlated to systolic PAP and mean PAP (Fig. 1 A). Arginine levels were not lower than normal, and lower levels of arginine were strongly related to higher levels of PAP, suggesting the availability of intracellular endogenous arginine to NO synthesis and vasodilation might be restricted in PAH. A growing body of data indicates that free methylarginines, endogenous inhibitors of NOS, may cause endothelial vasodilator dysfunction in individuals with coronary and peripheral arterial diseases. Here, asymmetric dimethylarginine (ADMA), N^G-monomethyl-L-arginine (L-NMMA), and symmetric dimethylarginine (SDMA) were not higher in PAH serum than controls (Fig. 1B ).

View larger version (20K): [in this window] [in a new window]   Figure 1. Levels of arginine, ADMA, L-NMMA, and SDMA, arginase activity, ornithine and arginine-to-ornithine ratio. A) There was significant inverse correlation between the level of arginine in PAH lung epithelial cells and systolic pulmonary artery pressure (r=–0.945). B) Levels of ADMA, L-NMMA and SDMA in serum of PAH (n=16) or healthy controls (n=14) were not increased in PAH serum as compared with healthy controls (P>0.05). C) Arginase activity was significantly higher in serum of PAH patients (n=15) compared with healthy controls (n=13), P<0.05. D) Arginine and ornithine levels in serum of PAH (n=16) or healthy controls (n=16) show a trend for lower arginine in PAH than healthy controls (P=0.06). E) The arginine-to-ornithine ratio, which reflects arginase activity, was significantly lower in PAH than controls (P=0.02). F) Correlation of arginase activity (mU/ml) and ornithine (µM) in serum of PAH (r=0.786, P<0.01, n=15).

3. High level of arginase activity and expression in PAH
Arginase, a critical enzyme in the urea cycle, converts arginine to ornithine and urea, and plays a regulatory role in NO synthesis by modulating the availability of arginine for NOS. Arginase activity was significantly higher in serum of PAH patients vs. healthy controls (Fig. 1C ). Since arginases are intracellular enzymes that appear in the circulation only after cell damage or death, an arginine-to-ornithine ratio has been suggested as a better measure of intracellular arginase activity. Serum arginine in PAH tended to be less than healthy controls and the arginine-to-ornithine ratio was significantly lower in PAH than controls, indicating greater intracellular arginase activity in PAH patients in vivo (Fig. 1D, E ). Serum ornithine levels were directly proportional to serum arginase activity (Fig. 1F ). Arginase activity was also significantly higher in lysates of bronchial and vascular tissue of PPH lungs as compared with bronchial and vascular tissue explanted from chronic obstructive pulmonary disease (COPD).

As PAH patients have significantly higher arginase activity compared with controls, cellular localization of arginase in human lung was investigated by immunohistochemical staining of PPH and healthy control lungs (n=5). Immunoreactivity for arginase was present in airway epithelium and vessel endothelium. No difference was observed in cellular distribution of arginase throughout the lungs of PPH or healthy controls. However, expression of arginase was visibly more prominent in endothelium of arteries and arterioles of PPH than healthy controls (Fig. 2 A–E).

View larger version (63K): [in this window] [in a new window]   Figure 2. Arginase localization in lung tissue and expression and activity in PPH PAEC. In PPH lung, strong positive immunoreactivity of arginase was present in the endothelium of artery (arrowheads) (A) and endothelium of a plexigenic area (arrowheads) (B). Mild positive staining of arginase was seen in airway epithelium (arrowheads) and vessel endothelium (arrowheads) of healthy control lung (C). Immunohistochemical staining for CD 31 in the laminar lining cells (arrowheads), confirming their endothelial origin (D, E). Original magnification: x200 or x400. F) NOS III, arginase II, arginase I, and caveolin 1 protein expression in PAEC. Lysates from PPH pulmonary artery endothelial cells (PPH-PAEC) (lane 2), healthy control PAEC (Ctrl-PAEC) (lane 1), PPH pulmonary artery smooth muscle cells (PPH-PASMC) (lane 4), and healthy control artery smooth muscle cells (Ctrl-ASMC) (lane 3) were analyzed by Western blot using anti-NOS III, arginase II, arginase I, and caveolin 1 Abs. Arginase II expression is higher in PPH than in control PAEC. G) Arginase activity was significantly higher in PPH PAEC vs. healthy control (P<0.01). NO production (NOx) was significantly lower in the ionomycin-stimulated supernatant of PAEC from PPH lung (*P<0.05, 1-tailed analysis) vs. healthy control. H) NO production was significantly higher in the ionomycin-stimulated supernatant of PPH PAEC preincubated with arginase inhibitor (S)-(2-boronoethyl)-L-cysteine-HCl (BEC) and/or L-arginine (*P<0.05).

Arginase protein expression/activity was definitively identified in PAH endothelial cells through the culture and analyses of primary pulmonary artery endothelial cells (PAEC) derived from explanted PPH lung (Fig. 2F-G ). Arginase II protein expression was significantly higher in PPH than in control PAEC but barely detectable in control or PPH pulmonary artery smooth muscle cells (PASMC) (Fig. 2F ). PAEC expressed trace detectable level of arginase I compared with high levels of NOS III and caveolin 1 protein in PPH and controls. Arginase activity in PPH PAEC lysates was 10-fold higher than controls (Fig. 2G ). Thus, PPH PAEC have increased expression of arginase II, even after ex vivo culture.

4. NO synthesis by PPH PAEC in culture is less than control PAEC
Previous studies have shown that overexpression of arginase in PAEC increases consumption of arginine, decreasing arginine availability to NOS for NO synthesis and vasodilation. To test whether NO release was reduced in PAEC from PPH endothelial cells with high-level arginase II expression as compared with control PAEC, NO synthesis was determined by measure of NO reaction products in supernatant overlying cells. Compared with that from healthy control, NO production was significantly lower in the ionomycin-stimulated supernatant of PAEC from PPH lung (Fig. 2G ). However, NO production was significantly increased in the ionomycin-stimulated supernatant of PPH PAEC preincubated with the arginase inhibitor BEC and/or L-arginine (Fig. 2H ). NO production by cells with overexpression of NOS II was lower in PPH than control PAEC, while NO in media overlying nonstimulated PPH or control PAEC transfected with pCMV-ß-Gal were similar. Thus, PPH PAEC produce lower NO that may account for the lower levels of NO in exhaled breath from PPH patients.

CONCLUSIONS AND SIGNIFICANCE

NO has been implicated in the pathogenesis of pulmonary hypertension. Previously we reported that NO and NO biochemical reaction products (NO₂^–, NO₃^–) are lower in the lungs of PPH individuals than healthy controls. Here, we show that low levels of NO in PPH are related to decreased NO synthesis. However, the low levels of NO in PAH are not due to decreased NOS expression as assessed by Western analyses and immunostaining. Our results indicate that alteration of the L-arginine metabolic pathway by increased arginase II is the mechanism reducing NO synthesis in PAH. Other studies have shown that arginase limits arginine availability for NO synthesis. The most direct evidence for arginase regulation of NO synthesis is that endothelial cells with stable overexpression of arginase I or arginase II drop intracellular arginine levels by 25%, and basal NO synthesis is reduced by 60%. Similarly, cells with arginase II overexpression, which are stimulated with endotoxin to induce NOS II, have 50% reduction in NO synthesis. Thus, arginase expressed at high abundance in cells overcomes catalytic limitations, consumes arginine, and limits NOS activity. Abnormalities in arginine metabolism have been implicated in neonatal pulmonary hypertension. Infants with pulmonary hypertension have decreased NO synthesis with half-normal levels of plasma arginine, due to decreased activity of a variant form of carbamoyl-phosphate synthetase, the rate-limiting enzyme of the urea cycle that leads to arginine synthesis. Although arginase and arginine metabolic pathways had not been studied in adult PPH, arginase activity is increased 2-fold in serum of sickle cell patients who have associated secondary pulmonary hypertension. Arginine supplementation has been used to augment NO synthesis for treatment of pulmonary hypertension (i.e., hypoxia-induced pulmonary hypertension in rodents is nearly abolished by daily injections of arginine, and oral or intravenous arginine generally reduces pulmonary pressure in PAH patients). Our studies provide a rationale for future therapeutic innovations beyond arginine supplementation, such as targeting the arginine metabolic pathways through specific inhibition of arginase, induction of arginine recycling, or uptake into cells.

View larger version (15K): [in this window] [in a new window]   Figure 3. Schematic diagram: impaired biosynthesis of NO in adult primary pulmonary hypertension. NOS converts L-arginine to NO and citrulline. Arginase converts arginine to ornithine and urea. Adult patients with pulmonary hypertension have an increase of the arginine consumptive pathway through arginase that leads to loss of pulmonary vasodilator (NO). Previous work has shown that decreased synthesis of arginine due to deficient carbamoyl phosphate synthase, the rate-limiting enzyme of the urea cycle, contributes to pulmonary hypertension of the neonate.

FOOTNOTES

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This Article Full Text (PDF) All Versions of this Article: 18/14/1746 04-2317fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by XU, W. Articles by ERZURUM, S. C. Search for Related Content PubMed PubMed Citation Articles by XU, W. Articles by ERZURUM, S. C.