Inducible Nitric Oxide Synthase Inhibition of Weibel-Palade Body Release in Cardiac Transplant Rejection

Qian, Zhiping; Gelzer-Bell, Ramona; Yang, Shui Xiang; Cao, Wangsen; Ohnishi, Tomokazu; Wąsowska, Barbara; Hruban, Ralph H.; Rodríguez, E. René; Baldwin, William M.; Lowenstein, Charles J.

doi:10.1161/hc4401.098471

Cited by 40 publications

(26 citation statements)

References 59 publications

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“…Our results show that endogenous NO then inhibits Weibel-Palade body exocytosis triggered by S1P itself or by other agonists. Previously, we have shown that NO inhibits exocytosis by directly nitrosylating N-ethylmaleimide-sensitive factor, a key regulator of vesicle trafficking (20,28). The present study shows that not only exogenous but also endogenous NO inhibits exocytosis.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that other agonists that increase eNOS expression or activity will also inhibit endothelial exocytosis. Furthermore, vascular expression of other NOS isoforms such as inducible NOS or neuronal NOS may also lead to regulation of endothelial exocytosis (20).…”

Section: Discussionmentioning

confidence: 99%

“…P-selectin is stored in Weibel-Palade bodies, endothelial storage granules that also contain von Willebrand factor (VWF) and tissue plasminogen activator (17)(18)(19)(20)(21)(22)(23)(24). Rapid exocytosis of WeibelPalade bodies is activated by thrombin, histamine, and other agonists.…”

mentioning

confidence: 99%

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Sphingosine 1-phosphate activates Weibel-Palade body exocytosis

Matsushita

Morrell

Lowenstein

2004

Proc. Natl. Acad. Sci. U.S.A.

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Sphingosine 1-phosphate (S1P) not only regulates angiogenesis, vascular permeability and vascular tone, but it also promotes vascular inflammation. However, the molecular basis for the proinflammatory effects of S1P is not understood. We now show that S1P activates endothelial cell exocytosis of Weibel-Palade bodies, releasing vasoactive substances capable of causing vascular thrombosis and inflammation. S1P triggers endothelial exocytosis in part through phospholipase C-␥ signal transduction. However, S1P also modulates endothelial cell exocytosis by activating endothelial nitric oxide synthase production of nitric oxide, which inhibits exocytosis. Thus S1P plays a dual role in regulating endothelial exocytosis, triggering pathways that both promote and inhibit endothelial exocytosis. Regulation of endothelial exocytosis may explain part of the proinflammatory effects of S1P.nitric oxide ͉ ceramide ͉ endothelial ͉ von Willebrand factor

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Sphingosine 1-phosphate activates Weibel-Palade body exocytosis

Matsushita

Morrell

Lowenstein

2004

Proc. Natl. Acad. Sci. U.S.A.

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“…It should be recognized; however, that iNOS appears to play an opposing beneficial role in chronic rejection (see Figure 1) as has been shown by genetic deletion of iNOS in models for aorta [25], heart [26,27] and kidney [28]. In this case, iNOS functions as an antiinflammatory effector molecule to limit chronic transplant-induced atherosclerosis and vasculopathy.…”

Section: Opposing Role Of Inos In Acute Vs Chronic Cardiac Transplanmentioning

confidence: 92%

The complex role of iNOS in acutely rejecting cardiac transplants

Pieper

Roza

2008

Free Radical Biology and Medicine

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This review summarizes the evidence for a detrimental role of nitric oxide (NO) derived from inducible NO synthase (iNOS) and/or reactive nitrogen species such as peroxynitrite in acutelyrejecting cardiac transplants. In chronic cardiac transplant rejection, iNOS may have an opposing beneficial component. The purpose of this review is primarily to address issues related to acute rejection which is a recognized risk factor for chronic rejection. The evidence for a detrimental role is based upon strategies involving non-selective NOS inhibitors, NO neutralizers, selective iNOS inhibitors and iNOS gene deletion in rodent models of cardiac rejection. The review is discussed in the context of the impact on various components including graft survival, histological rejection and cardiac function which may contribute in toto to the process of graft rejection. Possible limitations of each strategy are discussed in order to understand better the variance in published findings including issues related to the potential importance of cell localization of iNOS expression. Finally, the concept of a dual role of NO and its down-stream product, peroxynitrite, in rejection vs. immune regulation is discussed.

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“…However, NO and the reactive nitrogen intermediates produced by oxidation of NO can be harmful to the host. For example, NO plays a role in LPS-induced hypotension, LPSinduced lung damage, autoimmune vasculitis, autoimmune encephalomyelitis, autoimmune nephritis, and acute allograft rejection (13)(14)(15)(16)(17)(18)(19)(20)(21). Furthermore, NO can suppress inflammation and decrease cell injury.…”

mentioning

confidence: 99%

Nitric oxide inhibits exocytosis of cytolytic granules from lymphokine-activated killer cells

Ferlito

Irani

Faraday³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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NO inhibits cytotoxic T lymphocyte killing of target cells, although the precise mechanism is unknown. We hypothesized that NO decreases exocytosis of cytotoxic granules from activated lymphocytes. We now show that NO inhibits lymphokine-activated killer cell killing of K562 target cells. Exogenous and endogenous NO decreases the release of granzyme B, granzyme A, and perforin: all contents of cytotoxic granules. NO inhibits the signal transduction cascade initiated by cross-linking of the T cell receptor that leads to granule exocytosis. In particular, we found that NO decreases the expression of Ras, a critical signaling component within the exocytic pathway. Ectopic expression of Ras prevents NO inhibition of exocytosis. Our data suggest that Ras mediates NO inhibition of lymphocyte cytotoxicity and emphasize that alterations in the cellular redox state may regulate the exocytic signaling pathway.granzyme ͉ inflammation ͉ lymphocyte ͉ mitogen-activated protein kinases ͉ Ras N O plays a complex set of roles in the immune system (1-4). NO is generated from L-arginine by one of three isoforms of NO synthase (NOS): neuronal NOS (NOS1), endothelial NOS (NOS3), and inducible NOS (iNOS or NOS2) (5, 6). NO can act as an innate immune effector, inhibiting the replication of diverse pathogens such as Mycobacterium tuberculosis, Leishmania, and coxsackievirus (7-12). However, NO and the reactive nitrogen intermediates produced by oxidation of NO can be harmful to the host. For example, NO plays a role in LPS-induced hypotension, LPSinduced lung damage, autoimmune vasculitis, autoimmune encephalomyelitis, autoimmune nephritis, and acute allograft rejection (13-21). Furthermore, NO can suppress inflammation and decrease cell injury. For example, NO inhibits vascular inflammation in part by decreasing endothelial exocytosis of factors that would otherwise promote leukocyte adherence to the vessel wall (22). NO also modulates the immune response, inhibiting T lymphocyte proliferation and differentiation, B lymphocyte proliferation and antibody production, and immune cell production of cytokines (12).NO may also be able to modulate inflammation in part by regulating immune cell killing of target cells. Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells kill infected cells or tumor cells by several distinct pathways, including activation of the Fas͞Fas ligand pathway and exocytosis of cytolytic granules. These cytolytic granules contain perforin, serine proteases (including granzymes), and other effector molecules that promote death of target cells. When a T cell or NK cell recognizes its target, an immunological synapse is formed, a cluster of signaling, adhesion, and cytoskeletal proteins that includes the T cell receptor or a NK cell receptor, tyrosine kinases such as Lck and ZAP-70, and adaptor proteins such as LAT (linker of T cell activation) and . This cluster of signaling molecules activates downstream pathways, including Ras, Raf, MAPK͞ERK kinase (MEK), and ERK. The microtubule organizing center directs the...

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Inducible Nitric Oxide Synthase Inhibition of Weibel-Palade Body Release in Cardiac Transplant Rejection

Abstract: Background-Inducible nitric oxide synthase (iNOS, or NOS2)

Cited by 40 publications

References 59 publications

Sphingosine 1-phosphate activates Weibel-Palade body exocytosis

Sphingosine 1-phosphate activates Weibel-Palade body exocytosis

The complex role of iNOS in acutely rejecting cardiac transplants

Nitric oxide inhibits exocytosis of cytolytic granules from lymphokine-activated killer cells

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