Transfection of Short-Interfering RNA Silences Adhesion Molecule Expression on Cardiac Microvascular Cells

Walker, Thomas A.; Saup, Esther Katharina; Nolte, Andrea; Simon, Perikles; Kornberger, Angela; Steger, Volker; Adolph, O.; Wendel, HP

doi:10.1055/s-0030-1271142

Cited by 4 publications

(4 citation statements)

References 19 publications

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“…The administration of neutralizing VCAM-1 antibodies impairs breast cancer cell adhesion to endothelial cells, transmigration through endothelial monolayers and metastasis formation [ 56 , 60 , 65 ]. Alternatively, VCAM-1 in the endothelium also binds to monocytes and neutrophils [ 76 ] that may bind tumor cells. In fact, inhibition of PMNs infiltration can be achieved by pretreating PMNs with soluble vascular cell adhesion molecule-1 [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis

Koning,

Cordova,

Aguilar

et al. 2023

Biol Res

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Background Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown. Results We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases. Conclusions S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis

Koning,

Cordova,

Aguilar

et al. 2023

Biol Res

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“…15 In addition, it may be that local neutralization of adhesion molecules is not sufficient for modulating T cell trafficking, and more systemic administration may be able to improve graft survival by modulating immune cell-vasculature interactions at additional locations other than the allograft, such as in the draining lymphoid tissue. There may also be more effective means of selectin blockade than neutralizing antibodies as other methods for selectin neutralization have proven effective in prior studies, including use of siRNA 52,53 and selectin-knockout mice. 54,55 The modest increase in graft survival observed here may also be explained by considering the effect of E-selectin neutralization on antigen-presenting cells more closely, and in particular, its effect on tolerogenic dendritic cells.…”

Section: Discussionmentioning

confidence: 99%

E-Selectin Mediates Immune Cell Trafficking in Corneal Transplantation

et al. 2016

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Background Immune rejection continues to threaten all tissue transplants. Here we sought to determine whether P- and E- selectin mediate T cell recruitment in corneal transplantation and whether their blockade can reduce T cell graft infiltration and improve long-term corneal allograft survival. Methods In a murine model of allogeneic corneal transplantation, we used PCR and immunohistochemistry to investigate expression of P- and E-selectin in rejected versus accepted allografts, and lymph node flow cytometry to assess expression of selectin ligands by effector T cells. Using P- and E-selectin neutralizing antibodies we evaluated the effect of blockade on CD4 T cell recruitment, as well as the effect of anti-E selectin on long-term allograft survival. Results P- (93.3 fold, p<0.05) and E-selectin (17.1 fold, p<0.005) are upregulated in rejected versus accepted allogeneic transplants. T helper (Th)1 cells from hosts with accepted and rejected grafts express high levels of P-selectin glycoprotein ligand 1 and glycosylated CD43. In vivo blockade of P (0.47±0.03, p<0.05) and E selectin (0.49±0.1, p<0.05) reduced the number of recruited T cells compared to IgG control (0.98±0.1). Anti-E-selectin reduced the number of mature antigen-presenting cells trafficking to lymphoid tissue compared to control (6.96±0.9 vs. 12.67±0.5 p<0.05). Anti-E-selectin treatment delayed graft rejection and increased survival compared to control, although this difference did not reach statistical significance. Conclusions In a model of corneal transplantation, P- and E-selectin mediate T cell recruitment to the graft, E-selectin mediates APC trafficking to lymphoid tissue and blockade of E-selectin has a modest effect on improving long-term graft survival.

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“…Interfering VCAM-1 expression could be an effective approach toward the prevention and treatment of atherosclerosis and restenosis [22,89,90]. VCAM-1 is an adhesion molecule that is expressed by ECs for recruitment of leukocytes during inflammation.…”

Section: Sirna Strategy For Vascular Diseasementioning

confidence: 99%

Small-Nucleic-Acid-Based Therapeutic Strategy Targeting the Transcription Factors Regulating the Vascular Inflammation, Remodeling and Fibrosis in Atherosclerosis

Youn

Park

2015

IJMS

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Atherosclerosis arises when injury to the arterial wall induces an inflammatory cascade that is sustained by a complex network of cytokines, together with accumulation of lipids and fibrous material. Inflammatory cascades involve leukocyte adherence and chemotaxis, which are coordinated by the local secretion of adhesion molecules, chemotactic factors, and cytokines. Transcription factors are critical to the integration of the various steps of the cascade response to mediators of vascular injury, and are induced in a stimulus-dependent and cell-type-specific manner. Several small-nucleic-acid-based therapeutic strategies have recently been developed to target transcription factors: antisense oligodeoxynucleotides, RNA interference, microRNA, and decoy oligodeoxynucleotides. The aim of this review was to provide an overview of these particular targeted therapeutic strategies, toward regulation of the vascular inflammation, remodeling and fibrosis associated with atherosclerosis.

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Transfection of Short-Interfering RNA Silences Adhesion Molecule Expression on Cardiac Microvascular Cells

Abstract: This investigation demonstrates that liposomal transfection of HCMEC with specific siRNA sequences is capable of both repressing adhesion molecule expression and of reducing subsequent leukocyte-endothelial actions.

Cited by 4 publications

References 19 publications

S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis

S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis

E-Selectin Mediates Immune Cell Trafficking in Corneal Transplantation

Small-Nucleic-Acid-Based Therapeutic Strategy Targeting the Transcription Factors Regulating the Vascular Inflammation, Remodeling and Fibrosis in Atherosclerosis

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