Evaluating the relevance of the platelet transcriptome

Weyrich, Andrew S.; Zimmerman, Guy A.

doi:10.1182/blood-2003-05-1429

Cited by 19 publications

(22 citation statements)

References 10 publications

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“…Because our focus was a patient with thrombocytopenia, we did not adopt vigorous methods to eliminate leukocytes, as performed in some studies [10], or pool samples from multiple donors [19,20]. However, we demonstrate that the expression of signature genes attributed conventionally to other cell lines (although some may indeed be expressed in platelets as well [10,21,22]) is uniform and consistent across the patient and control profiles (Table S4). This strengthens our conclusion regarding the differential gene expression in our patient.…”

Section: Discussionmentioning

confidence: 88%

Decreased platelet expression of myosin regulatory light chain polypeptide (MYL9) and other genes with platelet dysfunction and CBFA2/RUNX1 mutation: insights from platelet expression profiling

Sun

Gorospe

Hoffman

et al. 2007

Journal of Thrombosis and Haemostasis

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Summary. We have reported on a patient with thrombocytopenia, impaired platelet aggregation, secretion, phosphorylation of pleckstrin and myosin light chain (MLC), and GPIIb–IIIa activation, associated with a heterozygous mutation in transcription factor CBFA2 (core binding factor A2, RUNX1 or AML1). To obtain insights into the abnormal platelet mechanisms and CBFA2‐regulated genes, we performed platelet expression profiling in four control subjects and the patient using the Affymetrix U133 GeneChips. In the patient, 298 probe sets were significantly downregulated at least 2‐fold. MLC regulatory polypeptide (MYL9 gene) was decreased ∼77‐fold; this is an important finding because agonist‐stimulated MLC phosphorylation is decreased in patient platelets. Genes downregulated ≥ 5‐fold include those involving calcium binding proteins (CABP5), ion transport (sodium/potassium/Ca exchanger, SLC24A3), cytoskeletal/microtubule proteins (erythrocyte membrane protein band 4.1‐like 3, EPB41L3; tropomyosin 1, TPM1; tubulin, alpha 1, TUBA1), signaling proteins (RAB GTPase activating protein 1‐like, RABGAP1L; β3‐endonexin, ITGB3 BP) and chemokines (platelet factor 4 variant 1, PF4V1; chemokine CXCL5, CXCL5). These and other downregulated genes are relevant to the patient's platelet defects in function and production. These studies provide the first proof of concept that platelet expression profiling can be applied to obtain insights into the molecular basis of inherited platelet defects.

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Section: Discussionmentioning

confidence: 88%

Decreased platelet expression of myosin regulatory light chain polypeptide (MYL9) and other genes with platelet dysfunction and CBFA2/RUNX1 mutation: insights from platelet expression profiling

Sun

Gorospe

Hoffman

et al. 2007

Journal of Thrombosis and Haemostasis

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“…Circulating platelets not only respond to extracellular signals by upregulating expression of preformed molecules but also engage in new protein synthesis. 25 Alternatively, megakaryocytes may respond to soluble signals unique to the ACS patient. The RNA profile of circulating platelets reflects such changes in bone marrow megakaryocytes.…”

Section: Discussionmentioning

confidence: 99%

Platelet Expression Profiling and Clinical Validation of Myeloid-Related Protein-14 as a Novel Determinant of Cardiovascular Events

et al. 2006

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Background-Platelets participate in events that immediately precede acute myocardial infarction. Because platelets lack nuclear DNA but retain megakaryocyte-derived mRNAs, the platelet transcriptome provides a novel window on gene expression preceding acute coronary events. Methods and Results-We profiled platelet mRNA from patients with acute ST-segment-elevation myocardial infarction (STEMI, nϭ16) or stable coronary artery disease (nϭ44). The platelet transcriptomes were analyzed and single-gene models constructed to identify candidate genes with differential expression. We validated 1 candidate gene product by performing a prospective, nested case-control study (nϭ255 case-control pairs) among apparently healthy women to assess the risk of future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) associated with baseline plasma levels of the candidate protein. Platelets isolated from STEMI and coronary artery disease patients contained 54 differentially expressed transcripts. The strongest discriminators of STEMI in the microarrays were CD69 (odds ratio 6.2, PϽ0.001) and myeloid-related protein-14 (MRP-14; odds ratio 3.3, Pϭ0.002). Plasma levels of MRP-8/14 heterodimer were higher in STEMI patients (17.0 versus 8.0 g/mL, PϽ0.001). In the validation study, the risk of a first cardiovascular event increased with each increasing quartile of MRP-8/14 (P trend Ͻ0.001) such that women with the highest levels had a 3.8-fold increase in risk of any vascular event (PϽ0.001).Risks were independent of standard risk factors and C-reactive protein. Conclusions-The

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“…37 Recent studies by Healy and colleagues 38 on the platelet transcriptome of acute and stable coronary heart disease patients revealed the upregulated expression of CD69 and myeloid-related protein in the platelets of patients with acute cardiovascular events. This work provides evidence for the ability of circulating platelets to modulate their transcriptome in disease conditions in response to extracellular stress signaling.…”

Section: Discussionmentioning

confidence: 99%

Amplified Expression Profiling of Platelet Transcriptome Reveals Changes in Arginine Metabolic Pathways in Patients With Sickle Cell Disease

et al. 2007

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Background-In sickle cell disease, ischemia-reperfusion injury and intravascular hemolysis produce endothelial dysfunction and vasculopathy characterized by reduced nitric oxide and arginine bioavailability. Recent functional studies of platelets in patients with sickle cell disease reveal a basally activated state, which suggests that pathological platelet activation may contribute to sickle cell disease vasculopathy. Methods and Results-Studies were therefore undertaken to examine transcriptional signaling pathways in platelets that may be dysregulated in sickle cell disease. We demonstrate and validate in the present study the feasibility of comparative platelet transcriptome studies on clinical samples from single donors by the application of RNA amplification followed by microarray-based analysis of 54 000 probe sets. Data mining an existing microarray database, we identified 220 highly abundant genes in platelets and a subset of 72 relatively platelet-specific genes, defined by Ͼ10-fold increased expression compared with the median of other cell types in the database with amplified transcripts. The highly abundant platelet transcripts found in the present study included 82% or 70% of platelet-abundant genes identified in 2 previous gene expression studies on nonamplified mRNA from pooled or apheresis samples, respectively. On comparing the platelet gene expression profiles in 18 patients with sickle cell disease in steady state to those of 12 black control subjects, at a 3-fold cutoff and 5% false-discovery rate, we identified Ϸ100 differentially expressed genes, including multiple genes involved in arginine metabolism and redox homeostasis. Further characterization of these pathways with real-time polymerase chain reaction and biochemical assays revealed increased arginase II expression and activity and decreased platelet polyamine levels. Conclusions-The present studies suggest a potential pathogenic role for platelet arginase and altered arginine and polyamine metabolism in sickle cell disease and provide a novel framework for the study of disease-specific platelet biology.

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Evaluating the relevance of the platelet transcriptome

Cited by 19 publications

References 10 publications

Decreased platelet expression of myosin regulatory light chain polypeptide (MYL9) and other genes with platelet dysfunction and CBFA2/RUNX1 mutation: insights from platelet expression profiling

Decreased platelet expression of myosin regulatory light chain polypeptide (MYL9) and other genes with platelet dysfunction and CBFA2/RUNX1 mutation: insights from platelet expression profiling

Platelet Expression Profiling and Clinical Validation of Myeloid-Related Protein-14 as a Novel Determinant of Cardiovascular Events

Amplified Expression Profiling of Platelet Transcriptome Reveals Changes in Arginine Metabolic Pathways in Patients With Sickle Cell Disease

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