Publications by authors named "Linsey J F Peters"

10 Publications

  • Page 1 of 1

Immunomodulatory Nanomedicine for the Treatment of Atherosclerosis.

J Clin Med 2021 Jul 20;10(14). Epub 2021 Jul 20.

Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, 52074 Aachen, Germany.

Atherosclerosis is the main underlying cause of cardiovascular diseases (CVDs), which remain the number one contributor to mortality worldwide. Although current therapies can slow down disease progression, no treatment is available that can fully cure or reverse atherosclerosis. Nanomedicine, which is the application of nanotechnology in medicine, is an emerging field in the treatment of many pathologies, including CVDs. It enables the production of drugs that interact with cellular receptors, and allows for controlling cellular processes after entering these cells. Nanomedicine aims to repair, control and monitor biological and physiological systems via nanoparticles (NPs), which have been shown to be efficient drug carriers. In this review we will, after a general introduction, highlight the advantages and limitations of the use of such nano-based medicine, the potential applications and targeting strategies via NPs. For example, we will provide a detailed discussion on NPs that can target relevant cellular receptors, such as integrins, or cellular processes related to atherogenesis, such as vascular smooth muscle cell proliferation. Furthermore, we will underline the (ongoing) clinical trials focusing on NPs in CVDs, which might bring new insights into this research field.
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http://dx.doi.org/10.3390/jcm10143185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306310PMC
July 2021

Transcriptome signature of miRNA-26b KO mouse model suggests novel targets.

BMC Genom Data 2021 Jun 30;22(1):23. Epub 2021 Jun 30.

Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.

Background: MicroRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. One of the miRNAs that has been shown to play a role in various pathologies like cancer, neurological disorders and cardiovascular diseases is miRNA-26b. However, these studies only demonstrated rather ambiguous associations without revealing a causal relationship. Therefore, the aim of this study is to establish and validate a mouse model which enables the elucidation of the exact role of miRNA-26b in various pathologies.

Results: A miRNA-26b-deficient mouse model was established using homologous recombination and validated using PCR. miRNA-26b-deficient mice did not show any physiological abnormalities and no effects on systemic lipid levels, blood parameters or tissue leukocytes. Using next generation sequencing, the gene expression patterns in miRNA-26b-deficient mice were analyzed and compared to wild type controls. This supported the already suggested role of miRNA-26b in cancer and neurological processes, but also revealed novel associations of miRNA-26b with thermogenesis and allergic reactions. In addition, detailed analysis identified several genes that seem to be highly regulated by miRNA-26b, which are linked to the same pathological conditions, further confirming the role of miRNA-26b in these pathologies and providing a strong validation of our mouse model.

Conclusions: miRNA-26b plays an important role in various pathologies, although causal relationships still have to be established. The described mouse model of miRNA-26b deficiency is a crucial first step towards the identification of the exact role of miRNA-26b in various diseases that could identify miRNA-26b as a promising novel diagnostic or even therapeutic target in a broad range of pathologies.
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http://dx.doi.org/10.1186/s12863-021-00976-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243710PMC
June 2021

Tyrosine Kinase Inhibitor Sunitinib Delays Platelet-Induced Coagulation: Additive Effects of Aspirin.

Thromb Haemost 2021 Jun 15. Epub 2021 Jun 15.

Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.

Background:  Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of sunitinib on thrombus formation induced by other TK-dependent receptors, and (2) the effects under coagulating conditions. Cardiovascular disease is a comorbidity in cancer patients, resulting in possible aspirin treatment. Sunitinib and aspirin are associated with increased bleeding risk, and therefore we also investigated (3) the synergistic effects of these compounds on thrombus and fibrin formation.

Methods:  Blood or isolated platelets from healthy volunteers or cancer patients were incubated with sunitinib and/or aspirin or vehicle. Platelet activation was determined by TK phosphorylation, flow cytometry, changes in [Ca], aggregometry, and whole blood perfusion over multiple surfaces, including collagen with(out) tissue factor (TF) was performed.

Results:  Sunitinib reduced thrombus formation and phosphatidylserine (PS) exposure under flow on collagen type I and III. Also, sunitinib inhibited glycoprotein VI-induced TK phosphorylation and Ca elevation. Upon TF-triggered coagulation, sunitinib decreased PS exposure and fibrin formation. In blood from cancer patients more pronounced effects of sunitinib were observed in lung and pancreatic as compared to neuroglioblastoma and other cancer types. Compared to sunitinib alone, sunitinib plus aspirin further reduced platelet aggregation, thrombus formation, and PS exposure on collagen under flow with(out) coagulation.

Conclusion:  Sunitinib suppresses collagen-induced procoagulant activity and delays fibrin formation, which was aggravated by aspirin. Therefore, we urge for awareness of the combined antiplatelet effects of TKIs with aspirin, as this may result in increased risk of bleeding.
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http://dx.doi.org/10.1055/s-0041-1730312DOI Listing
June 2021

Adipocyte calcium sensing receptor is not involved in visceral adipose tissue inflammation or atherosclerosis development in hyperlipidemic Apoe mice.

Sci Rep 2021 May 17;11(1):10409. Epub 2021 May 17.

Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.

The calcium sensing receptor (CaSR) is a G-protein coupled receptor that especially plays an important role in the sensing of extracellular calcium to maintain its homeostasis. Several in-vitro studies demonstrated that CaSR plays a role in adipose tissue metabolism and inflammation, resulting in systemic inflammation and contributing to atherosclerosis development. The aim of this study was to investigate whether adipocyte CaSR plays a role in adipose tissue inflammation in-vivo and atherosclerosis development. By using a newly established conditional mature adipocyte specific CaSR deficient mouse on a hyperlipidemic and atherosclerosis prone Apoe background it could be shown that CaSR deficiency in adipocytes does neither contribute to initiation nor to progression of atherosclerotic plaques as judged by the unchanged lesion size or composition. Additionally, CaSR deficiency did not influence gonadal visceral adipose tissue (vAT) inflammation in-vivo, although a small decrease in gonadal visceral adipose cholesterol content could be observed. In conclusion, adipocyte CaSR seems not to be involved in vAT inflammation in-vivo and does not influence atherosclerosis development in hyperlipidemic Apoe mice.
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http://dx.doi.org/10.1038/s41598-021-89893-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128899PMC
May 2021

Adipocyte-Specific ACKR3 Regulates Lipid Levels in Adipose Tissue.

Biomedicines 2021 Apr 6;9(4). Epub 2021 Apr 6.

Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80337 Munich, Germany.

Dysfunctional adipose tissue (AT) may contribute to the pathology of several metabolic diseases through altered lipid metabolism, insulin resistance, and inflammation. Atypical chemokine receptor 3 (ACKR3) expression was shown to increase in AT during obesity, and its ubiquitous elimination caused hyperlipidemia in mice. Although these findings point towards a role of ACKR3 in the regulation of lipid levels, the role of adipocyte-specific ACKR3 has not yet been studied exclusively in this context. In this study, we established adipocyte- and hepatocyte-specific knockouts of in ApoE-deficient mice in order to determine its impact on lipid levels under hyperlipidemic conditions. We show for the first time that adipocyte-specific deletion of results in reduced AT triglyceride and cholesterol content in ApoE-deficient mice, which coincides with increased and increased expression. The role of adipocyte ACKR3 in lipid handling seems to be tissue-specific as hepatocyte ACKR3 deficiency did not demonstrate comparable effects. In summary, adipocyte-specific ACKR3 seems to regulate AT lipid levels in hyperlipidemic mice, which may therefore be a significant determinant of AT health. Further studies are needed to explore the potential systemic or metabolic effects that adipocyte ACKR3 might have in associated disease models.
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http://dx.doi.org/10.3390/biomedicines9040394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067615PMC
April 2021

MicroRNAs in Chronic Kidney Disease: Four Candidates for Clinical Application.

Int J Mol Sci 2020 Sep 7;21(18). Epub 2020 Sep 7.

Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Hospital, 52074 Aachen, Germany.

There are still major challenges regarding the early diagnosis and treatment of chronic kidney disease (CKD), which is in part due to the fact that its pathophysiology is very complex and not clarified in detail. The diagnosis of CKD commonly is made after kidney damage has occurred. This highlights the need for better mechanistic insight into CKD as well as improved clinical tools for both diagnosis and treatment. In the last decade, many studies have focused on microRNAs (miRs) as novel diagnostic tools or clinical targets. MiRs are small non-coding RNA molecules that are involved in post-transcriptional gene regulation and many have been studied in CKD. A wide array of pre-clinical and clinical studies have highlighted the potential role for miRs in the pathogenesis of hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, kidney tubulointerstitial fibrosis, and some of the associated cardiovascular complications. In this review, we will provide an overview of the miRs studied in CKD, especially highlighting miR-103a-3p, miR-192-5p, the miR-29 family and miR-21-5p as these have the greatest potential to result in novel therapeutic and diagnostic strategies.
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http://dx.doi.org/10.3390/ijms21186547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555601PMC
September 2020

Small Things Matter: Relevance of MicroRNAs in Cardiovascular Disease.

Front Physiol 2020 7;11:793. Epub 2020 Jul 7.

German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany.

MicroRNAs (miRNAs) are short sequences of non-coding RNA that play an important role in the regulation of gene expression and thereby in many physiological and pathological processes. Furthermore, miRNAs are released in the extracellular space, for example in vesicles, and are detectable in various biological fluids, such as serum, plasma, and urine. Over the last years, it has been shown that miRNAs are crucial in the development of several cardiovascular diseases (CVDs). This review discusses the (patho)physiological implications of miRNAs in CVD, ranging from cardiovascular risk factors (i.e., hypertension, diabetes, dyslipidemia), to atherosclerosis, myocardial infarction, and cardiac remodeling. Moreover, the intriguing possibility of their use as disease-specific diagnostic and prognostic biomarkers for human CVDs will be discussed in detail. Finally, as several approaches have been developed to alter miRNA expression and function (i.e., mimics, antagomirs, and target-site blockers), we will highlight the miRNAs with the most promising therapeutic potential that may represent suitable candidates for therapeutic intervention in future translational studies and ultimately in clinical trials. All in all, this review gives a comprehensive overview of the most relevant miRNAs in CVD and discusses their potential use as biomarkers and even therapeutic targets.
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http://dx.doi.org/10.3389/fphys.2020.00793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358539PMC
July 2020

B-Cell-Specific CXCR4 Protects Against Atherosclerosis Development and Increases Plasma IgM Levels.

Circ Res 2020 03 5;126(6):787-788. Epub 2020 Feb 5.

Pathology (E.P.C.v.d.V.), Cardiovascular Research Institute, Maastricht University, the Netherlands.

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http://dx.doi.org/10.1161/CIRCRESAHA.119.316142DOI Listing
March 2020

G-Protein Coupled Receptor Targeting on Myeloid Cells in Atherosclerosis.

Front Pharmacol 2019 22;10:531. Epub 2019 May 22.

Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany.

Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVDs), is a lipid-driven, inflammatory disease of the large arteries. therapy with statins and the more recently developed (PCSK9) inhibitors have improved health conditions among CVD patients by lowering (LDL) cholesterol. Nevertheless, a substantial part of these patients is still suffering and it seems that 'just' lipid lowering is insufficient. The results of the (CANTOS) have now proven that inflammation is a key driver of atherosclerosis and that targeting inflammation improves CVD outcomes. Therefore, the identification of novel drug targets and development of novel therapeutics that block atherosclerosis-specific inflammatory pathways have to be promoted. The inflammatory processes in atherosclerosis are facilitated by a network of immune cells and their subsequent responses. Cell networking is orchestrated by various (inflammatory) mediators which interact, bind and induce signaling. Over the last years, G-protein coupled receptors (GPCRs) emerged as important players in recognizing these mediators, because of their diverse functions in steady state but also and specifically during chronic inflammatory processes - such as atherosclerosis. In this review, we will therefore highlight a selection of these receptors or receptor sub-families mainly expressed on myeloid cells and their role in atherosclerosis. More specifically, we will focus on chemokine receptors, both classical and atypical, formyl-peptide receptors, the chemerin receptor 23 and the calcium-sensing receptor. When information is available, we will also describe the consequences of their targeting which may hold promising options for future treatment of CVD.
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http://dx.doi.org/10.3389/fphar.2019.00531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540917PMC
May 2019

Hematopoietic ChemR23 (Chemerin Receptor 23) Fuels Atherosclerosis by Sustaining an M1 Macrophage-Phenotype and Guidance of Plasmacytoid Dendritic Cells to Murine Lesions-Brief Report.

Arterioscler Thromb Vasc Biol 2019 04;39(4):685-693

From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Germany (E.P.C.v.d.V., M. Mandl, M. Müller, C.N., Y.J., M.H., S.G., L.J.F.P., S.M., O.S., M.D., C.W., Y.D.).

Objective- Expression of the chemokine-like receptor ChemR23 (chemerin receptor 23) has been specifically attributed to plasmacytoid dendritic cells (pDCs) and macrophages and ChemR23 has been suggested to mediate an inflammatory immune response in these cells. Because chemokine receptors are important in perpetuating chronic inflammation, we aimed to establish the role of ChemR23-deficiency on macrophages and pDCs in atherosclerosis. Approach and Results- ChemR23-knockout/knockin mice expressing eGFP (enhanced green fluorescent protein) were generated and after crossing with apolipoprotein E-deficient ( Apoe ChemR23 ) animals were fed a western-type diet for 4 and 12 weeks. Apoe ChemR23 mice displayed reduced lesion formation and reduced leukocyte adhesion to the vessel wall after 4 weeks, as well as diminished plaque growth, a decreased number of lesional macrophages with an increased proportion of M2 cells and a less inflammatory lesion composition after 12 weeks of western-type diet feeding. Hematopoietic ChemR23-deficiency similarly reduced atherosclerosis. Additional experiments revealed that ChemR23-deficiency induces an alternatively activated macrophage phenotype, an increased cholesterol efflux and a systemic reduction in pDC frequencies. Consequently, expression of the pDC marker SiglecH in atherosclerotic plaques of Apoe ChemR23 mice was declined. ChemR23-knockout pDCs also exhibited a reduced migratory capacity and decreased CCR (CC-type chemokine receptor)7 expression. Finally, adoptive transfer of sorted wild-type and knockout pDCs into Apoe recipient mice revealed reduced accumulation of ChemR23-deficient pDCs in atherosclerotic lesions. Conclusions- Hematopoietic ChemR23-deficiency increases the proportion of alternatively activated M2 macrophages in atherosclerotic lesions and attenuates pDC homing to lymphatic organs and recruitment to atherosclerotic lesions, which synergistically restricts atherosclerotic plaque formation and progression.
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http://dx.doi.org/10.1161/ATVBAHA.119.312386DOI Listing
April 2019
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