Abstract
Background: Tetraspanins and integrins are integral membrane proteins. Tetraspanins interact with integrins to modulate the dynamics of adhesion, migration, proliferation, and signaling in the form of membrane domains called tetraspanin-enriched microdomains (TEMs). TEMs also contain other cell adhesion proteins like immunoglobulin superfamily (IgSF) proteins and claudins. Cardiovascular functions of these TEM proteins have emerged and remain to be further revealed.Objectives: The aims of this study are to explore the roles of these TEM proteins in the cardiovascular system using bioinformatics tools and databases and to highlight the TEM proteins that may functionally associate with cardiovascular physiology and pathology.Methods: For human samples, three databases—GTEx, NCBI-dbGaP, and NCBI-GEO—were used for the analyses. The dbGaP database was used for GWAS analysis to determine the association between target genes and human phenotypes. GEO is an NCBI public repository that archives genomics data. GTEx was used for the analyses of tissue-specific mRNA expression levels and eQTL. For murine samples, GeneNetwork was used to find gene–phenotype correlations and gene–gene correlations of expression levels in mice. The analysis of cardiovascular data was the focus of this study.Results: Some integrins and tetraspanins, such as ITGA8 and Cd151, are highly expressed in the human cardiovascular system. TEM components are associated with multiple cardiovascular pathophysiological events in humans. GWAS and GEO analyses showed that human Cd82 and ITGA9 are associated with blood pressure. Data from mice also suggest that various cardiovascular phenotypes are correlated with integrins and tetraspanins. For instance, Cd82 and ITGA9, again, have correlations with blood pressure in mice.Conclusion: ITGA9 is related to blood pressure in both species. KEGG analysis also linked ITGA9 to metabolism and MAPK signaling pathway. This work provides an example of using integrated bioinformatics approaches across different species to identify the connections of structurally and/or functionally related molecules to certain categories of diseases.
Highlights
Tetraspanin-Enriched MicrodomainsTetraspanin-enriched microdomains (TEMs) are ubiquitously present in a variety of cells such as endothelial cells (ECs), vascular smooth muscle cells (VSMCs), leukocytes, and platelets
The expression level of each gene of tetraspanins and integrins in the human cardiovascular system was determined by Genotype-Tissue Expression (GTEx)
Tetraspanins CD151, CD81, TSPAN3, and CD9; integrins β5, β1, and αV; and integrin-associated protein Fermt2/Kindlin2 are relatively highly expressed (Table 1), this study/dataset did not dissect the distributions of these expressions in EC and/or VSMC compartments of the aortas
Summary
Tetraspanin-Enriched MicrodomainsTetraspanin-enriched microdomains (TEMs) are ubiquitously present in a variety of cells such as endothelial cells (ECs), vascular smooth muscle cells (VSMCs), leukocytes, and platelets. Formed by tetraspanins, TEMs contain other membrane proteins such as integrins, immunoglobulin superfamily (IgSF) proteins, and claudins [1] (Figure 1). Integrins are heterodimeric receptors mainly for extracellular matrices (ECMs), conducting both inside-out and outside-in signaling for various cellular functions [3] such as cell adhesion, migration, proliferation, and survival [4, 5]. Tetraspanins interact with integrins to modulate the dynamics of adhesion, migration, proliferation, and signaling in the form of membrane domains called tetraspanin-enriched microdomains (TEMs). TEMs contain other cell adhesion proteins like immunoglobulin superfamily (IgSF) proteins and claudins. Cardiovascular functions of these TEM proteins have emerged and remain to be further revealed
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