X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Leptin treatment has vasculo-protective effects in lipodystrophic mice
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 40 ( 2022-10-04)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 40 ( 2022-10-04)
    Abstract: Lipodystrophy syndromes (LDs) are characterized by loss of adipose tissue, metabolic complications such as dyslipidemia, insulin resistance, and fatty liver disease, as well as accelerated atherosclerosis. As a result of adipose tissue deficiency, the systemic concentration of the adipokine leptin is reduced. A current promising therapeutic option for patients with LD is treatment with recombinant leptin (metreleptin), resulting in reduced risk of mortality. Here, we investigate the effects of leptin on endothelial to mesenchymal transition (EndMT), which impair the functional properties of endothelial cells and promotes atherogenesis in LD. Leptin treatment reduced inflammation and TGF-β2–induced expression of mesenchymal genes and prevented impairment of endothelial barrier function. Treatment of lipodystrophic- and atherosclerosis-prone animals (Ldlr −/− ; aP2-nSrebp1c-Tg) with leptin reduced macrophage accumulation in atherosclerotic lesions, vascular plaque protrusion, and the number of endothelial cells with mesenchymal gene expression, confirming a reduction in EndMT in LD after leptin treatment. Treatment with leptin inhibited LD-mediated induction of the proatherosclerotic cytokine growth/differentiation factor 15 ( GDF15 ). Inhibition of GDF15 reduced EndMT induction triggered by plasma from patients with LD. Our study reveals that in addition to the effects on adipose tissue function, leptin treatment exerts beneficial effects protecting endothelial function and identity in LD by reducing GDF15 .
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2110374119
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 2
    Online Resource
    Online Resource
    Abstract 10192: Circular RNA Formation in the Failing Heart is Enhanced by the Reduction of Adenosine-to-Inosine RNA Editing
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Vol. 144, No. Suppl_1 ( 2021-11-16)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 144, No. Suppl_1 ( 2021-11-16)
    Abstract: Introduction: Adenosine-to-Inosine (A-to-I) RNA editing is a post-transcriptional modification process regulating RNA stability and alternative splicing. A-to-I RNA editing is conducted by the enzymes ADAR1 and ADAR2 and mainly targets Alu elements, primate-specific elements which have been associated with the formation of circular RNA (circRNA). Although differential expression of circRNAs has been studied in heart failure (HF), the extent of A-to-I RNA editing and consequences in the human heart remain largely unknown. Methods and Results: We analyzed RNA editing in human heart samples of HF (n=20) patients and controls (n=10) using RNA sequencing. We found a reduction of A-to-I RNA editing in intronic Alu elements of protein-coding genes in HF patients compared to controls. The majority (96%) of regulated circRNAs were upregulated. The predicted back-splice sites (BSS) of 20 circRNAs were validated by qPCR. The circRNA candidates correlated with RNA editing (R=0.47, P=0.02). Among the upregulated circRNAs, we identified two circular transcripts (circAKAP13) derived from the AKAP13 gene, which showed reduced A-to-I RNA editing in HF (-70.7%, n=20). In HF, ADAR2 was reduced (-68.2%) and ADAR1 was increased (7.41±0.13 -fold) on protein level (n=3-6). The knockdown of ADAR1 did not alter circRNA levels, whereas the knockdown of ADAR2 led to significantly upregulated levels of circAKAP13 (1.88±0.42 -fold, n=6). Consistently, ADAR2 overexpression reduced circAKAP13 expression (-41%, n=3). Using two mini-genes containing exons 15-19 of the AKAP13 gene and flanking Alu elements, we found convergent Alu elements enhancing circAKAP13 expression. Conclusion: In conclusion, these data describe the A-to-I RNA editome in the human heart for the first time. Reduced A-to-I RNA editing in HF patients is associated with elevated circRNA levels. We propose a primate-specific splicing mechanism mediated by A-to-I RNA editing in the human heart. These findings contribute to a better mechanistic understanding of A-to-I RNA editing in cardiac diseases.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.144.suppl_1.10192
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1466401-X
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 3
    Online Resource
    Online Resource
    Abstract 10579: Vascular Impairment by Trimethylamine N-Oxide (TMAO) Uptake and the First Description of a TMAO Transporter in Endothelial Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Vol. 144, No. Suppl_1 ( 2021-11-16)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 144, No. Suppl_1 ( 2021-11-16)
    Abstract: Introduction: Trimethylamine N-oxide (TMAO) derived from dietary sources has been linked to a higher risk of atherosclerotic disease. However, the underlying mechanisms are not fully understood. Impairment of endothelial cells (ECs) by chronic inflammation or metabolic cues can lead to a loss of EC phenotype and function towards a mesenchymal cell type, a process contributing to atherosclerosis termed endothelial-to-mesenchymal transition (EndMT). Here, we investigate the potential uptake of TMAO and its impact on endothelial inflammation and EndMT. Methods & Results: Using tandem mass spectrometry, we found ECs to take up TMAO in a time-dependent manner (0.5 nmol/mg within 30 min rising to 5.8 nmol/mg TMAO/total protein after 24 h). The induction of ICAM1 (+26.5-fold) and E-Selectin (+77.7-fold, both p 〈 0.05) indicated an inflammatory activation of ECs after TMAO uptake. The prolonged treatment of ECs with TMAO for 3 days induced EndMT, as indicated by increase of the mesenchymal markers Calponin 1 (+11.9-fold) and SM22 (+8.6-fold) and by a concomitant downregulation of endothelial LYVE1 (-92%, all p 〈 0.05). Functionally, the EC barrier function was significantly impaired after prolonged TMAO treatment leading to an increase in vascular permeability (+2.36-fold). The multitude of known human solute carrier proteins were screened in ECs for identification of a potential TMAO transporter. Single-cell RNA-sequencing revealed the Endothelial TMAO Transporter 1 (ETT1) to be upregulated in inflammatory-activated ECs of the myocardium. Overexpression of ETT1 resulted in a 61.7% higher intracellular TMAO concentration in ECs after 30 min of treatment. Downregulation of ETT1 by siRNA prevented TMAO-induced inflammation (-112% induction of E-Selectin and -105% induction of ICAM1) and EndMT (-315% induction of SM22 and -533% induction of Calponin 1) and restored EC barrier function (-78% induction of permeability). Conclusions: In summary, our study identifies that TMAO uptake into human ECs causes increased inflammation and induces EndMT. The TMAO-mediated impairment of EC function is prevented by down-regulation of the newly identified TMAO transporter ETT1. Our findings may help to better understand the interaction of diet and atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.144.suppl_1.10579
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1466401-X
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 4
    Online Resource
    Online Resource
    Abstract 10966: Characterization of the Novel Cardiac Splicing Factor Slm2 in Heart Failure, Which Regulates Splicing of Titin
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Vol. 144, No. Suppl_1 ( 2021-11-16)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 144, No. Suppl_1 ( 2021-11-16)
    Abstract: Introduction: The versatility of the human genome is increased by the process of alternative mRNA splicing. Impaired splicing of the cardiac transcriptome is involved in the pathophysiology of heart failure. Especially, mutations in cardiac-specific splicing factors such as RBM20 cause severe forms of cardiomyopathy. Aim: We aimed to identify novel cardiomyopathy-associated splicing factors in the human heart using a score of myocardial tissue specificity including 53 human tissues and disease-associated expression changes in hearts of dilated cardiomyopathy (DCM) patients and controls. Methods & Results: We found the splicing factor Slm2 to be significantly upregulated on the mRNA and protein level in the human myocardium of patients diagnosed with DCM (1.88 and 5.3-fold, both P 〈 0.05). Reduction of Slm2 in vivo resulted in DCM in zebrafish and sarcomere irregularity and altered calcium cycling in human cardiomyocytes. Sequencing of RNAs bound to Slm2 isolated from diseased human hearts, revealed the interaction of Slm2 with important mRNA transcripts encoding for sarcomere constituents, such as troponin I, troponin T, tropomyosin and titin. In the failing human myocardium, Slm2 bound to an alternative titin mRNA variant including retained introns. In detail, Slm2 interacted with exons of the titin mRNA encoding for the PEVK region, which mediates flexibility and contractile properties of the heart muscle. Using a splice reporter assay, which contains parts of titin’s PEVK region, we found Slm2 mediating the splicing process of intron retention. Conclusion: Slm2 is a novel splicing factor in the diseased human myocardium, maintaining cardiomyocyte integrity and function by binding and splicing essential sarcomere constituents including titin.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.144.suppl_1.10966
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1466401-X
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
Nothing or not found what you are looking for? Please check your search query or use the Interlibrary Loan Search.
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages