TNF Induces Laminin-332-Encoding Genes in Endothelial Cells and Laminin-332 Promotes an Atherogenic Endothelial Phenotype
<p>Laminin–receptor interactions and their consequences. Schematic figure illustrating the interaction between laminins and their receptors, such as integrins, dystroglycans, Lutheran/basal cell adhesion molecule (Lu/BCAM), and melanoma cell adhesion molecule (MCAM/CD146), and the consequences of these interactions on the behavior and phenotype of the cells. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> "> Figure 2
<p>Major cells and cytokines of atherosclerotic plaques. A schematic figure illustrating the key cellular components and cytokines present within atherosclerotic plaques, including macrophages, vascular smooth muscle cells (VSMCs), and T cells. These cells contribute to the progression of atherosclerosis through various mechanisms. Upon the uptake of modified low-density lipoproteins (LDL), these cells secrete proinflammatory cytokines that act on different cell types, thereby accelerating the disease process. Among these cytokines, TNF is a potent activator of endothelial cells and plays a crucial role in modulating laminin gene expression. The figure also highlights potential inhibitors of these cytokines, offering insight into therapeutic strategies aimed at mitigating atherosclerotic progression. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> "> Figure 3
<p>TNF alters the mRNA expression of laminin-encoding genes in human endothelial cells. The mRNA expression of <span class="html-italic">LAMA1–5</span> (<b>a</b>–<b>e</b>), <span class="html-italic">LAMB1–4</span> (<b>f</b>–<b>i</b>), and <span class="html-italic">LAMC1</span> and <span class="html-italic">LAMC2</span> (<b>j</b>,<b>k</b>) in human endothelial cells exposed to 50 ng/mL of TNF-α for 4–48 h. The data are presented as mean ± SD of 3 independent experiments. One-way ANOVA followed by Dunnett’s multiple comparison were performed to calculate statistical significance. All the timepoints are compared to CTL. * <span class="html-italic">p</span>-value < 0.05, ** <span class="html-italic">p</span>-value < 0.01, *** <span class="html-italic">p</span>-value < 0.001.</p> "> Figure 4
<p>TNF alters the protein expression of LN332-encoding genes in human endothelial cells. Protein expression of LN332-encoding genes in HUVECs following treatment with TNF for 48 h (<b>a</b>–<b>d</b>). Figure (<b>a</b>) shows representative cropped Western blot image of LN332 chains, while Figures (<b>b</b>–<b>d</b>) show relative levels of LN332 chains from three independent experiments (CTL = 1 a.u.). Full-length Western blot images are shown in <a href="#app1-ijms-25-08699" class="html-app">Supplementary Figure S1</a>. The data are presented as mean ± SD. Student’s <span class="html-italic">t</span>-test was conducted to calculate statistical significance. * <span class="html-italic">p</span>-value < 0.05.</p> "> Figure 5
<p>Human endothelial cells cultured on LN332 display irregular shape, appears loosely connected and express less tight junction protein claudin-5. A representative PECAM-1 and VE-cadherin staining of human endothelial cells cultured on uncoated or LN332-coated surfaces for 48 h (<b>a</b>). mRNA and protein expression of claudin-5 in human HUVECs cultured on plastic, LN332, or LN511 for 48 h (<b>b</b>). The data are presented as mean ± SD of three independent experiments. One-way ANOVA and Bonferoni test were performed to assess statistical significance. Cells cultured on laminins are compared to cells cultured on plastic (uncoated). * <span class="html-italic">p</span>-value < 0.05, ** <span class="html-italic">p</span>-value < 0.01.</p> "> Figure 6
<p>Endothelial cells cultured on LN332 have higher expression and secretion of leukocyte adhesion molecules. mRNA expression of <span class="html-italic">E-selectin</span> (<b>a</b>), <span class="html-italic">ICAM-1</span> (<b>b</b>), <span class="html-italic">VCAM-1</span> (<b>c</b>), and <span class="html-italic">PECAM-1</span> (<b>d</b>) in human endothelial cells cultured on uncoated plastic, LN332, or the normal vascular laminin isoform, LN511, for 48 h. Protein levels of E-selectin (<b>e</b>), ICAM-1 (<b>f</b>), and VCAM-1 (<b>g</b>) in cell lysate and protein levels of ICAM-1 (<b>h</b>) and VCAM-1 (<b>i</b>) in supernatant of endothelial cells cultured on plastic, LN332, or LN511 for 48 h. The data are presented as mean ± SD of three independent experiments. One-way ANOVA and Bonferroni test were performed to calculate statistical significance. * <span class="html-italic">p</span>-value < 0.05, ** <span class="html-italic">p</span>-value < 0.01 and *** <span class="html-italic">p</span>-value < 0.001 comparing cells cultured on laminins to cells cultured on uncoated plastic.</p> "> Figure 7
<p>Human endothelial cells cultured on LN332 have higher expression and secretion of chemokines. Volcano plot showing significantly up- and downregulated proteins in supernatant of endothelial cells cultured on LN332 in relation to cells cultured on uncoated surface for 48 h as measured by OLINK’s proximity extension assay (<b>a</b>). Red-colored dots indicate proteins that are significantly upregulated, and green-colored dots indicate proteins that are significantly downregulated (Log2FC < 0.58 and false discovery rate 5%). Heatmap showing comparison of proteins detected in supernatant from cells cultured on LN332 with cells cultured on uncoated or LN511-coated surfaces (<b>b</b>). Gene expression of upregulated chemokines in human endothelial cells cultured on plastic, LN332, or LN511 for 48 h determined by qRT-PCR (<b>c</b>–<b>h</b>). OLINK data are presented as mean log2 fold change of four independent experiments. qRT-PCR data are presented as mean ± SD of three independent experiments. One-way ANOVA and Bonferroni test were performed to calculate statistical significance for PCR data, whereas <span class="html-italic">t</span>-test and Benjamini–Hochberg tests were used to evaluate statistical significance for OLINK data. Cells cultured on laminins are compared to cells cultured on plastic (uncoated). ** <span class="html-italic">p</span>-value < 0.01, *** <span class="html-italic">p</span>-value < 0.001.</p> "> Figure 8
<p>Enrichment analysis predicts that human endothelial cells cultured on LN332 release proteins that regulate leucocyte migration/chemotaxis. Ingenuity Pathway Analysis (IPA) was used to perform enrichment analysis of differentially regulated proteins (Log2FC ± 0.58 and false discovery rate 20%) released from human endothelial cells cultured on LN332 compared to cells cultured on plastic. A bar graph showing the top ten functions (Z-score > 1.5) enriched by LN332 regulated proteins with their respective <span class="html-italic">p</span>-values (−Log10) (<b>a</b>). Proteins that enriched the functions “chemotaxis of leucocytes” (<b>b</b>) “and recruitment of phagocytes” or “migration of monocytes” (<b>c</b>) are presented with their respective predicted impacts on the activation state of the functions. The red color indicates upregulation in release of proteins while green indicates downregulation. Orange lines indicate that a protein leads to predicted activation of function, while yellow lines show disagreement between the state of differentially regulated protein expression and the predicted sate of function. The gray lines indicate that no prediction could be made.</p> "> Figure 9
<p>Monocytes tend to migrate more towards supernatant from endothelial cells cultured on LN332 and leukocytes adhere more to endothelial cells cultured on LN332. In vitro migration of CD14<sup>+</sup> monocytes towards the supernatant from endothelial cells cultured on plastic, LN332, or LN511 performed in Boyden’s transwell system (<b>a</b>) (n = 5). Adhesion of leukocytes to endothelial cells cultured on plastic, LN332, or LN511 (<b>b</b>) (n = 3). The data are presented as mean ± SD. One-way ANOVA followed by Bonferroni test were performed to calculate statistical significance. * <span class="html-italic">p</span>-value < 0.05 comparing cells cultured on laminins to cells cultured on uncoated plastic.</p> "> Figure 10
<p>LN332-encoding genes’ transcripts are elevated and correlate with TNF in human carotid atherosclerotic lesions. Gene expression of <span class="html-italic">LAMA3</span> (<b>a</b>), <span class="html-italic">LAMB3</span> (<b>b</b>), and <span class="html-italic">LAMC2</span> (<b>c</b>) in human carotid atherosclerotic tissues and adjacent macroscopically intact tissues (n = 32). Pearson’s correlation of <span class="html-italic">LAMA3</span> (<b>d</b>), <span class="html-italic">LAMB3</span> (<b>e</b>), and <span class="html-italic">LAMC2</span> (<b>f</b>) with <span class="html-italic">TNF</span> in human carotid atherosclerotic lesions (n = 32). Solid line indicates Pearson’s correlation coefficient (r), and dashed line indicates 95% confidence band of the best-fit line. Data are acquired from human carotid atheroma gene expression (accession number, GSE43292). <span class="html-italic">p</span>-value smaller than 0.05 is considered statistically significant.</p> ">
Abstract
:1. Introduction
2. Results
2.1. TNF Alters Laminin Gene Expression in HUVECs
2.2. TNF Induces the Expression of Laminin Genes That Make up the LN332 Isoform
2.3. HUVECs Cultured on LN332 Display Altered Morphology and Compromised Integrity
2.4. LN332 Induces the Expression and Secretion of Leukocyte Adhesion Molecules
2.5. HUVECs Cultured on LN332 Exhibit Increased Chemokine Secretion
2.6. HUVECs Cultured on LN332 Facilitate Migration of Monocytes and Adhesion of PBMCs In Vitro
2.7. LN332-Encoding Genes are Elevated in Carotid Atherosclerotic Lesions and Correlate with TNF
3. Discussion
4. Materials and Methods
4.1. Cell Culturing and Treatment
4.2. Quantitative Real Time-PCR
4.3. ELISA
4.4. Western Blot
4.5. Migration Assay
4.6. OLINK Proteomics and Ingenuity Pathway Analysis (IPA)
4.7. Adhesion Assay
4.8. Immunocytochemistry
4.9. Human Carotid Atheroma Gene Expression Data
4.10. Statistics
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Hayderi, A.; Zegeye, M.M.; Meydan, S.; Sirsjö, A.; Kumawat, A.K.; Ljungberg, L.U. TNF Induces Laminin-332-Encoding Genes in Endothelial Cells and Laminin-332 Promotes an Atherogenic Endothelial Phenotype. Int. J. Mol. Sci. 2024, 25, 8699. https://doi.org/10.3390/ijms25168699
Hayderi A, Zegeye MM, Meydan S, Sirsjö A, Kumawat AK, Ljungberg LU. TNF Induces Laminin-332-Encoding Genes in Endothelial Cells and Laminin-332 Promotes an Atherogenic Endothelial Phenotype. International Journal of Molecular Sciences. 2024; 25(16):8699. https://doi.org/10.3390/ijms25168699
Chicago/Turabian StyleHayderi, Assim, Mulugeta Melkie Zegeye, Sare Meydan, Allan Sirsjö, Ashok Kumar Kumawat, and Liza U. Ljungberg. 2024. "TNF Induces Laminin-332-Encoding Genes in Endothelial Cells and Laminin-332 Promotes an Atherogenic Endothelial Phenotype" International Journal of Molecular Sciences 25, no. 16: 8699. https://doi.org/10.3390/ijms25168699