We investigate the role of chemokines that orchestrate inflammatory cell recruitment and function during atherogenesis, as well as related epigenetic modifications and non-coding RNAs (ncRNAs).
- We are particularly interested in chemokine receptors, related cytokines and microRNAs with novel regulatory functions. We study mechanisms of regulation and function of epigenetic modifications and DNA damage, especially those charged to protein coding and ncRNAs, in triggering arterial phenotype and their involvement in the development of vascular diseases, such as atherosclerosis. We focus also on non-canonical receptors and ncRNA interactions in metabolic syndromes.
- Another aspect of our research is role of neurovascular crosstalk in cardiovascular disease.
- Our goal is to shed light on the relevance of molecular signatures in the development of vascular diseases and to unveil their possible applications as therapeutic or diagnostic/prognostic tools in patients with cardiovascular diseases
LATEST NEWS FROM THE LAB
- Non-canonical functional paradigms of microRNAs.
Synopsis of the miRNA-disengagement approach: Some MIRNA genes are located in the proximity of cell type-specific enhancers/superenhancers. Target site blocker (TSB) oligonucleotides preventing the interaction of cell-specific miRNAs with ubiquitously expressed transcripts offer the opportunity for cell-specific gene enhancement. By this approach, a TSB averting miR-206 from repressing CXCR4 in the cells of the vessel wall (i.e., endothelial and smooth muscle cells) to promote antiatherogenic features, without off-target effects in myeloid cells that do not express miR-206.
Micronuclei and genomic stability
Chromosomal aberrations and DNA damage characterize proliferating cells and may lead to the formation of extranuclear structures named micronuclei (MN). We have previously identified that endothelial cell proliferation is regulated through the Notch and Wnt/β-catenin signalling pathways through the fine-tune balance mediated by a novel lncRNA, named lncWDR59. More recently, we studied the effect of unbalanced proliferation in genomic instability and in promoting the accumulation of DNA damage in MN upon atherogenic stimuli. Ongoing research focuses on the contribution of genetic signatures physiologically relocated in MN, including those encoding for protein coding and lncRNAs, on arterial predisposition to plaque formation. In addition, research focuses on the contribution of atherogenic components in the generation of mutations and damages in DNA relocated in MN. The goal is to explore the molecular mechanisms involved in MN formation, including lncRNAs and proteins, like the cytosolic dsDNA sensor cGAS, with the aim of exploiting their use to preserve genomic stability, prevent endothelial dysfunction and atherosclerosis.
Genomic instability and autophagy
Genomic errors are enhanced during atherosclerosis and can relocate in extranuclear structures named micronuclei (MN), which can be subjected to autophagic degradation. We have previously reported that MN and DNA damage are enhanced, and that autophagy is impaired in endothelial cells lining arterial trees during atherosclerosis. Autophagy machinery sustain endothelial cell viability by a non-canonical trafficking of miR-126-5p into the nucleus that limits the proteolytic activity of caspase 3 and apoptosis. More recently, we studied the role of autophagy in the maintenance of genomic stability and in limiting the accumulation of MN with DNA damage upon atherogenic stimuli. Ongoing research focuses on the contribution of autophagy-related molecules, like LC3 and ATG5, and of the cytosolic dsDNA sensor cGAS in the detection and removal of MN, with the aim of exploiting their use to preserve genomic stability and prevent endothelial dysfunction and atherosclerosis.
Long non-coding RNAs and genomic stability in adipocytes
LncRNAs are RNA transcripts longer than 200 nucleotides that do not translate into proteins but contribute to cell biology by epigenetic regulation, miRNA sponging, and direct protein interactions.
We have previously identified a novel target for atherogenic miR-103-3p, named lncWDR59, trapped in the RISC complex to inhibit the endothelial proliferation and to promote the accumulation of DNA damage and plaque development.
More recently, we studied the role of miR-103:lncWDR59 axis in the maintenance of genomic stability and in limiting the anti-to-proatherogenic switch of adipose tissue. Ongoing research focuses on the contribution of lncWDR59 in limiting the accumulation of DNA damage of anti-atherogenic genes in adipocytes, with the aim of exploiting its use to prevent adipocyte dysfunction and atherosclerosis.
- Non-canonical role of orphan GPR26 in inflammation and metabolism
Diabetes is the ninth leading cause of death and increases the risk of cardiovascular diseases. Hyperglycaemia, as a hallmark of diabetes, acts as a potent stimulator of inflammatory condition by activating endothelial cells and by dysregulating monocyte activation. G-protein couple receptors (GPCRs) can both exacerbate and promote inflammatory resolution.
We have previously reported that orphan GPR26 is able to protect monocytes from hyperglycaemic conditions by limiting the activation of pro-inflammatory pathways.
More recently, we studied a non-canonical role of orphan GPR26 in mitochondrial recycling and endothelial metabolism upon hyperglycaemic and atherogenic stimuli. Ongoing research focuses on the contribution of GPR26 in the maintenance of proper mitophagy by localizing on mitochondria membrane upon metabolic stressors, as well as on its role in regulating endothelial metabolism upon atherogenic stimuli. The aim is to exploit its use to preserve mitochondrial function and prevent endothelial dysfunction.
- Effects of auditory stimulation, aging and ganglion remodelling in vascular inflammation
Adventitial arterial lymphoid organs (ATLOs) of atherosclerotic arteries interface and communicate with neurons and that this crosstalk markedly affects disease severity. This is mediated via the peripheral nervous system, creating a hardwired artery-brain circuit (ABC) connected to brain regions including the amygdala and capable of sensing and affecting vascular inflammation. Auditory stimuli such as music have been shown to affect both the cardiovascular and nervous systems. Music-responsive excitatory neurons in the auditory cortex are wired to distinct regions of the auditory circuit to affect mechano-sensitivity in distinct body parts, e.g. analgesic sound stimulating thalamus and insular cortex, while music eliciting emotional pleasure can target the amygdala and hippocampus, regions implicated in controling vascular inflammation. Intriguingly, peripheral ganglia are inflamed and circuit-associated neurons are activated during atherosclerosis by inducing adventitial and perivascular axon neogenesis in contrast to cardiac denervation during aging. The extent and mechanisms as to how auditory or sensory stimuli can influence vascular and ganglionic inflammation is unknown.
- Effects of chemokine(-receptor) biology on leukocytes and vascular cells in cardiovascular diseases.
We recently described a proatherogenic role of the non-canonical CCL17-CCR8 ligand-receptor dyad, which suppresses atherorotective Tregs in atherosclerosis. Also, we could show that expression of the chemokine receptor CXCR4 on B1 cells controls IgM titers and thereby mediated atheroprotection underlining the importance of B1 cell–derived IgM in atheroprotection.
TEAM
GROUP MEMBERS
Ismail Cimen, former PostDoc
Döring Y, van der Vorst EPC, Weber C. Targeting immune cell recruitment in atherosclerosis. Nat Rev Cardiol 2024
Döring Y, van der Vorst EPC, Yan Y, Neideck C, Blanchet X, Jansen Y, Kemmerich M, Bayasgalan S, Peters LJF, Hristov M, Bidzhekov K, Yin C, Zhang X, Leberzammer J, Li Y, Park I, Kral M, Nitz K, Parma L, Gencer S, Habenicht AJR, Faussner A, Teupser D, Monaco C, Holdt L, Megens RTA, Atzler D, Santovito D, von Hundelshausen P, Weber C. Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis. Nat Cardiov Res 2024
Cimen I*, Natarelli L*, Kichi ZA, Henderson JM, Farina FM, Briem E,Aslani M, Megens RTA, Jansen Y, Mann-Fallenbuchel E, Gencer S, Duchêne J, Nazari-Jahantigh M, van der Vorst EPC, Enard W, Döring Y, Schober A, Santovito D, Weber C. Cell-specific microRNA disengagement therapy to boost arterial CXCR4 and limit atherosclerosis. Sci Tranls Med, 2023 *authors' equal contribution
Kichi ZA, Natarelli L, Sadeghian S, Boroumand MA, Behmanesh M, Weber C. Orphan GPR26 counteracts early phases of hyperglycemia-mediated monocyte activation and is suppressed in diabetic patients. Biomedicines, 2022
Santovito D*, Egea V*, Bidzhekov K*, Natarelli L*, Mourão A, Blanchet X, Wichapong K, Aslani M, Brunßen C, Horckmans M, Hristov M, Geerlof A, Lutgens E, Daemen MJAP, Hackeng T, Ries C, Chavakis T, Morawietz H, Naumann R, von Hundelshausen P, Steffens S, Duchêne J, Megens RTA, Sattler M, Weber C. Noncanonical inhibition of caspase-3 by a nuclear microRNA confers endothelial protection by autophagy in atherosclerosis. Science Translational Medicine, 2020 *authors´equal contribution
Natarelli L, Geißler C, Csaba G, Wei Y, Zhu M, di Francesco A, Hartmann P, Zimmer R, Schober A. miR-103 promotes endothelial maladaptation by targeting lncWDR59. Nature Communications, 2018
Wei Y, Corbalán-Campos J*, Gurung R*, Natarelli L, Zhu M, Exner N, Erhard F, Greulich F, Geißler C, Uhlenhaut NH, Zimmer R, Schober A. Dicer in Macrophages prevents atherosclerosis by promoting mitochondrial oxidative metabolism. Circulation, 2018