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Transcriptional profiling of left ventricle and peripheral blood mononuclear cells in a rat model of postinfarction heart failure.

Tulacz D, Mackiewicz U, Maczewski M, Maciejak A, Gora M, Burzynska B - BMC Med Genomics (2013)

Bottom Line: Rats with small, moderate, and large MI size were included into the experiment two months after the operation.In contrast, no significant gene expression changes were seen in LVs of rats with moderate or small MI that had compensated LV injury.Ceruloplasmin and tetraspanin 12 are potential convenient markers in readily obtainable PBMCs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland. mgora@ibb.waw.pl.

ABSTRACT

Background: Myocardial infarction (MI) often results in left ventricular (LV) remodeling followed by heart failure (HF). It is of great clinical importance to understand the molecular mechanisms that trigger transition from compensated LV injury to HF and to identify relevant diagnostic biomarkers. The aim of this study was to investigate gene expression in the LV and to evaluate their reflection in peripheral blood mononuclear cells (PBMCs).

Methods: MI was induced in rats by ligation of the proximal left coronary artery. Rats with small, moderate, and large MI size were included into the experiment two months after the operation. The development of heart failure was estimated by echocardiography and catheterization. Microarrays were used to compare the LV and PBMCs transcriptomes of control and experimental animals.

Results: Only rats with a large MI developed extensive LV remodeling and heart failure. 840 transcripts were altered in LV of failing hearts, and especially numerous were those associated with the extracellular matrix. In contrast, no significant gene expression changes were seen in LVs of rats with moderate or small MI that had compensated LV injury. We showed that ceruloplasmin was similarly overexpressed in the heart and blood in response to HF, whereas downregulation of tetraspanin 12 was significant only in the PBMCs.

Conclusion: A large size of infarcted area is critical for progression of LV remodeling and HF development, associated with altered gene expression in the heart. Ceruloplasmin and tetraspanin 12 are potential convenient markers in readily obtainable PBMCs.

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Highest scoring interaction network generated by Ingenuity Pathway Analysis for genes differentially expressed in PBMCs. The top network classified as “Cardiovascular System Development and Function, Cellular Function and Maintenance, Cellular Growth and Proliferation” is overlaid for cardiovascular diseases. Genes or gene products are represented as nodes, and the biological relationship between two nodes is represented as a line. Continuous lines indicate direct interactions, while dashed lines indicate indirect relationships. Upregulated and downregulated genes are shown in red and green shading respectively, with colour intensity related to the fold change in expression. White symbols indicate molecules absent in the analysed dataset but related with the dataset genes.
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Figure 5: Highest scoring interaction network generated by Ingenuity Pathway Analysis for genes differentially expressed in PBMCs. The top network classified as “Cardiovascular System Development and Function, Cellular Function and Maintenance, Cellular Growth and Proliferation” is overlaid for cardiovascular diseases. Genes or gene products are represented as nodes, and the biological relationship between two nodes is represented as a line. Continuous lines indicate direct interactions, while dashed lines indicate indirect relationships. Upregulated and downregulated genes are shown in red and green shading respectively, with colour intensity related to the fold change in expression. White symbols indicate molecules absent in the analysed dataset but related with the dataset genes.

Mentions: Another interesting gene responding to HF was tetraspanin 12 (Tspan12). In contrast to Cp, it was downregulated substantially in the PBMCs but showed no response in the heart tissue. Members of the tetraspanin superfamily regulate key cellular processes such as adhesion, migration, and fusion. Tetraspanins play particularly important roles in cancer, by modulating tumor cell growth. Tetraspanins are expressed in vascular and haematopoietic cells and are involved in both physiological and pathological processes related to angiogenesis, vascular injury, thrombosis, and haemostasis. Previous studies suggest that tetraspanins directly regulate the development and functioning of the vascular system and the pathogenesis of vascular diseases [45]. In addition, mutations in the Tspan12 gene are associated with familial exudative vitreoretinopathy, a human disease caused by failure of peripheral retinal vascularization. Our results for the first time linked directly Tspan12 downregulation with heart failure development. To better understand the biological relevance of this finding we performed an Ingenuity Pathway Analysis of the molecular interaction networks for the genes differentially expressed in PBMCs. The major functional network with the highest score (IPA score = 47) and with 20 up- or downregulated genes, including Tspan 12, was associated with Cardiovascular System Development and Function, Cellular Function and Maintenance, Cellular Growth and Proliferation (Figure 5). This network analysis indicates that altered expression of tetraspanin 12 and other identified molecules may result in a dysfunction of the cardiovascular system by disturbance of their direct and indirect functional interactions. Moreover, tetraspanin 12 was found recently to regulate the activity of membrane metalloproteinases, MT1-MMP/MMP14 [46] and ADAM10 (disintegrin and metalloproteinase domain-containing protein 10) [47]. Affected functions of MT1-MMP/MMP14 influence fibronectin proteolysis and extracellular matrix degradation. ADAM10 is responsible for the proteolytic release of the ectodomains of numerous protein substrates, including specific ligands of EGFR (epidermal growth factor receptor) regulating the subsequent EGFR-dependent signal transduction pathways involved in cardiac hypertrophy [48]. Interestingly, ADAM10 mediates also cleavage of corin that may be important in regulating corin activity and hence ANP processing [49].


Transcriptional profiling of left ventricle and peripheral blood mononuclear cells in a rat model of postinfarction heart failure.

Tulacz D, Mackiewicz U, Maczewski M, Maciejak A, Gora M, Burzynska B - BMC Med Genomics (2013)

Highest scoring interaction network generated by Ingenuity Pathway Analysis for genes differentially expressed in PBMCs. The top network classified as “Cardiovascular System Development and Function, Cellular Function and Maintenance, Cellular Growth and Proliferation” is overlaid for cardiovascular diseases. Genes or gene products are represented as nodes, and the biological relationship between two nodes is represented as a line. Continuous lines indicate direct interactions, while dashed lines indicate indirect relationships. Upregulated and downregulated genes are shown in red and green shading respectively, with colour intensity related to the fold change in expression. White symbols indicate molecules absent in the analysed dataset but related with the dataset genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4226214&req=5

Figure 5: Highest scoring interaction network generated by Ingenuity Pathway Analysis for genes differentially expressed in PBMCs. The top network classified as “Cardiovascular System Development and Function, Cellular Function and Maintenance, Cellular Growth and Proliferation” is overlaid for cardiovascular diseases. Genes or gene products are represented as nodes, and the biological relationship between two nodes is represented as a line. Continuous lines indicate direct interactions, while dashed lines indicate indirect relationships. Upregulated and downregulated genes are shown in red and green shading respectively, with colour intensity related to the fold change in expression. White symbols indicate molecules absent in the analysed dataset but related with the dataset genes.
Mentions: Another interesting gene responding to HF was tetraspanin 12 (Tspan12). In contrast to Cp, it was downregulated substantially in the PBMCs but showed no response in the heart tissue. Members of the tetraspanin superfamily regulate key cellular processes such as adhesion, migration, and fusion. Tetraspanins play particularly important roles in cancer, by modulating tumor cell growth. Tetraspanins are expressed in vascular and haematopoietic cells and are involved in both physiological and pathological processes related to angiogenesis, vascular injury, thrombosis, and haemostasis. Previous studies suggest that tetraspanins directly regulate the development and functioning of the vascular system and the pathogenesis of vascular diseases [45]. In addition, mutations in the Tspan12 gene are associated with familial exudative vitreoretinopathy, a human disease caused by failure of peripheral retinal vascularization. Our results for the first time linked directly Tspan12 downregulation with heart failure development. To better understand the biological relevance of this finding we performed an Ingenuity Pathway Analysis of the molecular interaction networks for the genes differentially expressed in PBMCs. The major functional network with the highest score (IPA score = 47) and with 20 up- or downregulated genes, including Tspan 12, was associated with Cardiovascular System Development and Function, Cellular Function and Maintenance, Cellular Growth and Proliferation (Figure 5). This network analysis indicates that altered expression of tetraspanin 12 and other identified molecules may result in a dysfunction of the cardiovascular system by disturbance of their direct and indirect functional interactions. Moreover, tetraspanin 12 was found recently to regulate the activity of membrane metalloproteinases, MT1-MMP/MMP14 [46] and ADAM10 (disintegrin and metalloproteinase domain-containing protein 10) [47]. Affected functions of MT1-MMP/MMP14 influence fibronectin proteolysis and extracellular matrix degradation. ADAM10 is responsible for the proteolytic release of the ectodomains of numerous protein substrates, including specific ligands of EGFR (epidermal growth factor receptor) regulating the subsequent EGFR-dependent signal transduction pathways involved in cardiac hypertrophy [48]. Interestingly, ADAM10 mediates also cleavage of corin that may be important in regulating corin activity and hence ANP processing [49].

Bottom Line: Rats with small, moderate, and large MI size were included into the experiment two months after the operation.In contrast, no significant gene expression changes were seen in LVs of rats with moderate or small MI that had compensated LV injury.Ceruloplasmin and tetraspanin 12 are potential convenient markers in readily obtainable PBMCs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland. mgora@ibb.waw.pl.

ABSTRACT

Background: Myocardial infarction (MI) often results in left ventricular (LV) remodeling followed by heart failure (HF). It is of great clinical importance to understand the molecular mechanisms that trigger transition from compensated LV injury to HF and to identify relevant diagnostic biomarkers. The aim of this study was to investigate gene expression in the LV and to evaluate their reflection in peripheral blood mononuclear cells (PBMCs).

Methods: MI was induced in rats by ligation of the proximal left coronary artery. Rats with small, moderate, and large MI size were included into the experiment two months after the operation. The development of heart failure was estimated by echocardiography and catheterization. Microarrays were used to compare the LV and PBMCs transcriptomes of control and experimental animals.

Results: Only rats with a large MI developed extensive LV remodeling and heart failure. 840 transcripts were altered in LV of failing hearts, and especially numerous were those associated with the extracellular matrix. In contrast, no significant gene expression changes were seen in LVs of rats with moderate or small MI that had compensated LV injury. We showed that ceruloplasmin was similarly overexpressed in the heart and blood in response to HF, whereas downregulation of tetraspanin 12 was significant only in the PBMCs.

Conclusion: A large size of infarcted area is critical for progression of LV remodeling and HF development, associated with altered gene expression in the heart. Ceruloplasmin and tetraspanin 12 are potential convenient markers in readily obtainable PBMCs.

Show MeSH
Related in: MedlinePlus