Cell Cycle Regulation of Smooth Muscle Cells—Searching for Inhibitors of Neointima Formation: Is Combretastatin A4 an Alternative to Sirolimus and Paclitaxel?

Spira, Daniel; Grözinger, Gerd; Domschke, Nicole; Bantleon, Rüdiger; Schmehl, Jörg; Wiskirchen, Jakub; Wiesinger, Benjamin

doi:10.1016/j.jvir.2015.05.025

Cited by 5 publications

(3 citation statements)

References 20 publications

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“…SMC proliferation has been shown to be an initial event in response to vascular injury, contributing to neointima formation in various animal models of TV 17 . Elucidating the molecular mechanisms of the observed therapeutic effects, we analyzed cyclin D2 expression as a regulatory protein of the cell cycle 18 in the transplanted aortic tissue. Compared to control groups, grafts transduced with AAV9SLR expressing hpAP-1 consensus dONs exhibited a significant 2.6-fold decline (p < 0.05) and 3-fold (p < 0.01) decline in cyclin D2-positive SMC population in the neointima compared to control and mutated AAV, respectively (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts

Remes

Franz

Mohr

et al. 2019

Molecular Therapy - Methods & Clinical Development

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Transplant vasculopathy (TV), characterized by obstructive lesions in affected vessels, represents one of the long-term complications of cardiac transplantation. Activation of the transcription factor activator protein-1 (AP-1) is implicated in smooth muscle cell (SMC) phenotypic switch from contractile to synthetic function, increasing the migration and proliferation rate of these cells. We hypothesize that adeno-associated virus (AAV)-mediated delivery of an RNA hairpin AP-1 decoy oligonucleotide (dON) might effectively ameliorate TV severity in a mouse aortic allograft model. Aortic allografts from DBA/2 mice ex vivo transduced with modified AAV9-SLR carrying a targeting peptide within the capsid surface were transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg BW) was administered daily. AP-1 dONs were intracellularly expressed in the graft tissue as small hairpin RNA proved by fluorescent in situ hybridization. Explantation after 30 days and histomorphometric evaluation revealed that AP-1 dON treatment significantly reduced intima-to-media ratio by 41.5% (p < 0.05) in the grafts. In addition, expression of adhesion molecules, cytokines, as well as numbers of proliferative SMCs, matrix metalloproteinase-9-positive cells, and inflammatory cell infiltration were significantly decreased in treated aortic grafts. Our findings demonstrate the feasibility, efficacy, and specificity of the anti-AP-1 RNA dON approach for the treatment of allograft vasculopathy in an animal model. Moreover, the AAV-based approach in general provides the possibility to achieve a prolonged delivery of nucleic-acids-based therapeutics in to the blood vessel wall.

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Section: Resultsmentioning

confidence: 99%

AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts

Remes

Franz

Mohr

et al. 2019

Molecular Therapy - Methods & Clinical Development

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“…A wealth of evidence has emerged that two related, multisubunit E3 ubiquitin ligase enzymes, the Anaphase Promoting Complex (APC) and the Skp1-Cullin1-F-box complex (SCF), have been considered as the major driving forces governing cell cycle progression [26]. The initial role of Cdc20 was elucidated primarily in regulating cell cycle progression after it was discovered nearly half a century ago [27].…”

Section: Discussionmentioning

confidence: 99%

Integration of Gene Expression Profile Data to Verify Hub Genes of Patients with Stanford A Aortic Dissection

Wang

et al. 2019

BioMed Research International

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Thoracic aortic dissection (TAD) is a catastrophic disease worldwide, but the pathogenic genes and pathways are largely unclear. This study aims at integrating two gene expression profile datasets and verifying hub genes and pathways involved in TAD as well as exploring potential molecular mechanisms. We will combine our mRNAs expression profile (6 TAD tissues versus 6 non-TAD tissues) and GSE52093 downloaded from the Gene Expression Omnibus (GEO) database. The two mRNAs expression profiles contained 13 TAD aortic tissues and 11 non-TAD tissues. The two expression profile datasets were integrated and we found out coexpression of differentially expressed genes (DEGs) using bioinformatics methods. The gene ontology and pathway enrichment of DEGs were performed by DAVID and Kyoto Encyclopedia of Genes and Genomes online analyses, respectively. The protein-protein interaction networks of the DEGs were constructed according to the data from the STRING database. Cytohubber calculating result shows the top 10 hub genes with CDC20, AURKA, RFC4, MCM4, TYMS, MCM2, DLGAP5, FANCI, BIRC5, and POLE2. Module analysis revealed that TAD was associated with significant pathways including cell cycle, vascular smooth muscle contraction, and adrenergic signaling in cardiomyocytes. The qRT-PCR result showed that the expression levels of all the hub genes were significantly increased in OA samples (p < 0.05), and these candidate genes could be used as potential diagnostic biomarkers and therapeutic targets of TAD.

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“…It may be a newer antiproliferative drug which can be used for drug-eluting stents[28]. Another drug called MiR-21 modulates the post stenting inflammatory response.…”

Section: Desmentioning

confidence: 99%

Organ transplantation and drug eluting stents: Perioperative challenges

Dalal¹

2016

WJT

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Patients listed for organ transplant frequently have severe coronary artery disease (CAD), which may be treated with drug eluting stents (DES). Everolimus and zotarolimus eluting stents are commonly used. Newer generation biolimus and novolimus eluting biodegradable stents are becoming increasingly popular. Patients undergoing transplant surgery soon after the placement of DES are at increased risk of stent thrombosis (ST) in the perioperative period. Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor such as clopidogrel, prasugrel and ticagrelor is instated post stenting to decrease the incident of ST. Cangrelor has recently been approved by Food and Drug Administration and can be used as a bridging antiplatelet drug. The risk of ischemia vs bleeding must be considered when discontinuing or continuing DAPT for surgery. Though living donor transplant surgery is an elective procedure and can be optimally timed, cadaveric organ availability is unpredictable, therefore, discontinuation of antiplatelet medication cannot be optimally timed. The type of stent and timing of transplant surgery can be of utmost importance. Many platelet function point of care tests such as Light Transmittance Aggregrometry, Thromboelastography Platelet Mapping, VerifyNow, Multiple Electrode Aggregrometry are used to assess bleeding risk and guide perioperative platelet transfusion. Response to allogenic platelet transfusion to control severe intraoperative bleeding may differ with the antiplatelet drug. In stent thrombosis is an emergency where management with either a drug eluting balloon or a DES has shown superior outcomes. Post-transplant complications often involved stenosis of an important vessel that may need revascularization. DES are now used for endovascular interventions for transplant orthotropic heart CAD, hepatic artery stenosis post liver transplantation, transplant renal artery stenosis following kidney transplantation, etc. Several antiproliferative drugs used in the DES are inhibitors of mammalian target of rapamycin. Thus they are used for post-transplant immunosuppression to prevent acute rejection in recipients with heart, liver, lung and kidney transplantation. This article describes in detail the various perioperative challenges encountered in organ transplantation surgery and patients with drug eluting stents.

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Cell Cycle Regulation of Smooth Muscle Cells—Searching for Inhibitors of Neointima Formation: Is Combretastatin A4 an Alternative to Sirolimus and Paclitaxel?

Cited by 5 publications

References 20 publications

AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts

AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts

Integration of Gene Expression Profile Data to Verify Hub Genes of Patients with Stanford A Aortic Dissection

Organ transplantation and drug eluting stents: Perioperative challenges

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