scholarly journals Nitric oxide formation in acutely rejecting cardiac allografts correlates with GTP cyclohydrolase I activity

2005 ◽  
Vol 391 (3) ◽  
pp. 541-547 ◽  
Author(s):  
Galen M. Pieper ◽  
Vani Nilakantan ◽  
Nadine L. N. Halligan ◽  
Ashwani K. Khanna ◽  
Gail Hilton ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Graft Rejection ◽  
Ex Vivo ◽  
No Production ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Protein Levels ◽  
Acute Graft Rejection ◽  
Cardiac Allografts ◽  
Acute Graft

Inducible nitric oxide synthase (iNOS) is a prominent component of the complex array of mediators in acute graft rejection. While NO production is determined by iNOS expression, BH4 (tetrahydrobiopterin), a cofactor of iNOS synthesized by GTP cyclohydrolase I, has been considered critical in sustaining NO production. In the present study, we examined time-dependent changes in iNOS and GTP cyclohydrolase I in rat cardiac allografts. The increase in iNOS protein and mRNA in allografts was similar at POD4 (post-operative day 4) and POD6. However, the peak increase in intragraft NO level at POD4 was not sustained at POD6. This disparity could not be explained by any decrease in iNOS enzyme activity measured ex vivo with optimal amounts of substrate and cofactors. Lower iNOS activity could be explained by changes in total biopterin levels in allografts at POD4 that was decreased to baseline at POD6. Changes in biopterin production correlated with lower GTP cyclohydrolase I protein levels but not by any change in GTP cyclohydrolase I mRNA. Functionally, allografts displayed bradycardia and distended diastolic and systolic dimensions at POD6 but not at POD4. Likewise, histological rejection scores were increased at POD4 but with a secondary increased stage at POD6. It is hypothesized that the dissimilar amounts of NO at early and later stages of rejection is due to uncoupling of iNOS arising from disproportionate synthesis of BH4. These findings provide insight into a potential pathway regulating NO bioactivity in graft rejection. Such knowledge may potentially assist in the design of newer strategies to prevent acute graft rejection.

scholarly journals Interleukin 1β and cAMP trigger the expression of GTP cyclohydrolase I in rat renal mesangial cells

1996 ◽  
Vol 318 (2) ◽  
pp. 665-671 ◽  
Author(s):  
Christoph PLÜSS ◽  
Ernst R. WERNER ◽  
Nenad BLAU ◽  
Helmut WACHTER ◽  
Josef PFEILSCHIFTER
Keyword(s):  
Half Life ◽  
Mesangial Cells ◽  
Interleukin 1Β ◽  
No Production ◽  
Mrna Levels ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Protein Levels ◽  
Rabbit Polyclonal Antibody ◽  
Stimulation Of

Endogenous synthesis of tetrahydrobiopterin (BH4) is an important requirement for cytokine-stimulated nitric oxide (NO) production in mesangial cells. We have shown that inducible NO synthase is expressed in mesangial cells in response to two principal classes of activating signals, inflammatory cytokines such as interleukin 1β (IL-1β) and agents that elevate cellular levels of cAMP [Kunz, Mühl, Walker and Pfeilschifter (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 5387–5391]. In the present paper we demonstrate that IL-1β and cAMP similarly increase the steady-state mRNA levels of GTP cyclohydrolase I (EC 3.5.4.16), the rate-limiting enzyme in BH4 biosynthesis, as measured by a sensitive and quantitative nuclease protection assay. Stimulation of cells with a combination of IL-1β plus cAMP revealed an additive induction profile of GTP cyclohydrolase I mRNA. Message stability studies established that GTP cyclohydrolase I mRNA induced by cAMP has a longer half-life than the IL-1β-induced message. Moreover, cAMP exposure markedly prolonged the half-life of GTP cyclohydrolase I mRNA, from 1.5 to 3.4 h. In a next step we generated a rabbit polyclonal antibody against rat GTP cyclohydrolase I expressed in Escherichia coli and demonstrated that IL-1β and cAMP elevated GTP cyclohydrolase I protein levels in mesangial cells. Furthermore, IL-1β and cAMP led to a marked increase in GTP cyclohydrolase I activity and to increased accumulation of biopterin in mesangial cells. Combinations of IL-1β and cAMP resulted in a synergistic stimulation of GTP cyclohydrolase I activity. This may suggest that, in addition to transcriptional and post-transcriptional regulation, there is a prominent post-translational modulation of enzyme activity.

Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency

2000 ◽  
Vol 349 (1) ◽  
pp. 353-356 ◽  
Author(s):  
Cynthia J. MEININGER ◽  
Rebecca S. MARINOS ◽  
Kazuyuki HATAKEYAMA ◽  
Raul MARTINEZ-ZAGUILAN ◽  
Jose D. ROJAS ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
De Novo ◽  
Diabetic Rats ◽  
Bb Rat ◽  
No Production ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Bb Rats ◽  
Metabolic Basis ◽  
Rate Limiting

Endothelial cells (EC) from diabetic BioBreeding (BB) rats have an impaired ability to produce NO. This deficiency is not due to a defect in the constitutive isoform of NO synthase in EC (ecNOS) or alterations in intracellular calcium, calmodulin, NADPH or arginine levels. Instead, ecNOS cannot produce sufficient NO because of a deficiency in tetrahydrobiopterin (BH4), a cofactor necessary for enzyme activity. EC from diabetic rats exhibited only 12% of the BH4 levels found in EC from normal animals or diabetes-prone animals which did not develop disease. As a result, NO synthesis by EC of diabetic rats was only 18% of that for normal animals. Increasing BH4 levels with sepiapterin increased NO production, suggesting that BH4 deficiency is a metabolic basis for impaired endothelial NO synthesis in diabetic BB rats. This deficiency is due to decreased activity of GTP-cyclohydrolase I, the first and rate-limiting enzyme in the de novo biosynthesis of BH4. GTP-cyclohydrolase activity was low because of a decreased expression of the protein in the diabetic cells.

scholarly journals Acute graft rejection in a high-risk corneal transplant following COVID-19 vaccination: A case report

2021 ◽  
Vol 69 (12) ◽  
pp. 3757
Author(s):  
DipaliP Parmar ◽  
PawanV Garde ◽  
SarjakM Shah ◽  
PradnyaK Bhole
Keyword(s):  
Case Report ◽  
High Risk ◽  
Graft Rejection ◽  
Corneal Transplant ◽  
Acute Graft Rejection ◽  
Acute Graft

Acute Graft Rejection

2022 ◽  
pp. 259-274
Author(s):  
Rajesh Fogla ◽  
Deepak Soni
Keyword(s):  
Graft Rejection ◽  
Acute Graft Rejection ◽  
Acute Graft

scholarly journals Independent risk factors predicting acute graft rejection in cardiac transplant recipients treated by triple drug immunosuppression

1989 ◽  
Vol 98 (6) ◽  
pp. 1113-1121 ◽  
Author(s):  
Günther Laufer ◽  
Johannes Miholic ◽  
Axel Laczkovics ◽  
Gregor Wollenek ◽  
Christoph Holzinger ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Rejection ◽  
Cardiac Transplant ◽  
Transplant Recipients ◽  
Acute Graft Rejection ◽  
Independent Risk Factors ◽  
Acute Graft

ELISA ANTI-HLA ANTIBODY SCREENING IDENTIFIES NON-COMPLEMENT-FIXING ANTIBODIES RESPONSIBLE FOR ACUTE GRAFT REJECTION. A CASE REPORT

1996 ◽  
Vol 23 (5) ◽  
pp. 383-387 ◽  
Author(s):  
A. Nanni-Costa ◽  
M. P. Scolari ◽  
S. Iannelli ◽  
A. Vangelista ◽  
A. Buscaroli ◽  
...  
Keyword(s):  
Case Report ◽  
Graft Rejection ◽  
Antibody Screening ◽  
Acute Graft Rejection ◽  
Hla Antibody ◽  
Acute Graft
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