Microarray Analysis of Peripheral Blood Cells in Pulmonary Arterial Hypertension, Surrogate to Biopsy

Bull, Todd; Coldren, Chris D.; Nana‐Sinkam, Patrick; Sotto-Santiago, Sylk; Moore, Matthew; Voelkel, Norbert F.; Geraci, Mark W.

doi:10.1378/chest.128.6_suppl.584s

Cited by 5 publications

(6 citation statements)

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“…One such tissue source may be lymphocytes and their derived lymphoblast cell lines. In an increasing number of studies, investigators have demonstrated that the transcriptional signatures found in either lymphoblasts or lymphoblast cell lines are predictive of complex “medical” illnesses including hyperlipidemia, hypertension, and arthritis [Barnes et al, 2004; Morello et al, 2004; Bull et al, 2005]. Since nearly 82% of the genes expressed in the CNS are expressed in peripheral blood and the expression of genes in peripheral blood is affected by “environmental conditions,” if environmental or gene–environmental interactions are important in the etiology of a disorder, then it is possible that peripheral blood cells could serve as a biosensor or sentinel of disease vulnerability [Liew et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional profiling of lymphoblast lines from subjects with panic disorder

Philibert

Crowe

Ryu

et al. 2007

American J of Med Genetics Pt B

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In attempts to isolate genetic vulnerability factors for panic disorder (PD), a number of investigators have used genome-wide linkage or association analyses. But these attempts have been only modestly successful which suggests that alternative approaches may be needed to define the biology of PD. Therefore, using recently developed genome-wide gene expression profiling, we explored whether transcriptional signatures associated with PD are present in lymphoblast cell line. The expression of 2,469 transcripts in lymphoblast cell lines from 16 subjects was arithmetically increased in every line and significantly increased overall and 354 transcripts was arithmetically decreased in every cell line and significantly decreased overall as compared to those lymphoblast lines from 17 subjects without a history of behavioral illness. Further sex specific analyses showed that in those 10 lines derived from female probands, the expression of a further 67 transcripts was arithmetically increased in every line and significantly increased overall and a further 332 transcripts was arithmetically decreased in every cell line and significantly decreased. Conversely, in cell lines from the six male probands, the expression of an additional 212 was arithmetically increased in every line and significantly increased overall and a further 332 transcripts was arithmetically decreased in every cell line. We conclude that lymphoblast cell lines derived from subjects with PD have significant, partially sex dependent changes in gene transcription. Further studies are necessary to correlate these changes in these hemopoetically derived cells with those changes postulated to occur in the CNS in association with PD.

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Section: Introductionmentioning

confidence: 99%

Transcriptional profiling of lymphoblast lines from subjects with panic disorder

Philibert

Crowe

Ryu

et al. 2007

American J of Med Genetics Pt B

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“…Idiopathic PH has an estimated annual incidence of 1-2 per million (1) with mutations of the bone morphogenetic protein receptor type 2 gene (BMPR2) identified in ϳ50% of cases of familial PH (7). However, because only 20% of persons with a BMPR2 mutation develop PH (32), external stimuli, coupled with a susceptible genetic profile, likely contribute to the majority of PH cases (5,9,17,43).Currently several agents have proven efficacy in PH: anticoagulants, calcium channel blockers, prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors (2). Despite advances with new therapeutics, PH remains a devastating disease, because most approved therapies are expensive, fail to reverse vascular remodeling, and consequently offer only limited improvement in exercise capacity.…”

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confidence: 99%

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confidence: 99%

Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Moreno‐Vinasco

Gomberg‐Maitland

Maitland

et al. 2008

Physiological Genomics

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Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics 33: 278 -291, 2008. First published February 26, 2008 doi:10.1152/physiolgenomics.00169.2007.-Pulmonary hypertension (PH) and cancer pathology share growth factor-and MAPK stressmediated signaling pathways resulting in endothelial and smooth muscle cell dysfunction and angioproliferative vasculopathy. In this study, we assessed sorafenib, an antineoplastic agent and inhibitor of multiple kinases important in angiogenesis [VEGF receptor (VEGFR)-1-3, PDGF receptor (PDGFR)-␤, Raf-1 kinase] as a potential PH therapy. Two PH rat models were used: a conventional hypoxia-induced PH model and an augmented PH model combining dual VEGFR-1 and -2 inhibition (SU-5416, single 20 mg/kg injection) with hypoxia. In addition to normoxiaexposed control animals, four groups were maintained at 10% inspired O 2 fraction for 3.5 wk (hypoxia/vehicle, hypoxia/SU-5416, hypoxia/ sorafenib, and hypoxia/SU-5416/sorafenib). Compared with normoxic control animals, rats exposed to hypoxia/SU-5416 developed hemodynamic and histological evidence of severe PH while rats exposed to hypoxia alone displayed only mild elevations in hemodynamic values (pulmonary vascular and right ventricular pressures). Sorafenib treatment (daily gavage, 2.5 mg/kg) prevented hemodynamic changes and demonstrated dramatic attenuation of PH-associated vascular remodeling. Compared with normoxic control rats, expression profiling (Affymetrix platform) of lung RNA obtained from hypoxia [false discovery rate (FDR) 6.5%]-and hypoxia/SU-5416 (FDR 1.6%)-challenged rats yielded 1,019 and 465 differentially regulated genes (fold change Ͼ1.4), respectively. A novel molecular signature consisting of 38 differentially expressed genes between hypoxia/SU-5416 and hypoxia/SU-5416/sorafenib (FDR 6.7%) was validated by either real-time RT-PCR or immunoblotting. Finally, immunoblotting studies confirmed the upregulation of the MAPK cascade in both PH models, which was abolished by sorafenib. In summary, sorafenib represents a novel potential treatment for severe PH with the MAPK cascade a potential canonical target. microarrays; SU-5416; bioinformatics PULMONARY ARTERIAL HYPERTENSION (PH) is characterized by a progressive increase in pulmonary arterial pressure (PAP) with a mean pressure of Ͼ25 mmHg at rest or 30 mmHg during exercise (43), with severe PH exhibiting PAP values Ͼ50 mmHg (2, 59). Severe PH manifests as both an acute and a chronic presentation, with chronic PH leading to progressive right ventricular (RV) systolic pressure overload and ventricular dilatation, resulting in gradual RV dysfunction, heart failure, and death (21). Idiopathic PH has an estimated annual incidence of 1-2 per million (1) with mutations of the bone morphogenetic protein receptor type 2 gene (BMPR2) identified in ϳ50% of cases of familial PH (7). However, because only 20% of persons with a BMPR2 mutation develop PH (32), external stimuli, coupled with a susceptible genetic profile,...

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“…Clearly, other genetic polymorphisms and environmental factors are necessary to initiate the pathological sequence that leads to disease. As external stimuli coupled with undefined genetic susceptibility are likely responsible for the majority of PH cases, 5,8–11 this complexity lends itself to the use of high-throughput technologies such as gene microarrays, allowing efficient and accurate simultaneous assessment of the expression of thousands of genes. This technology has been most successfully employed in the investigation of cancer, including the classification of histologically indistinct tumor types with different natural histories.…”

Section: Genetic Studies In Pulmonary Hypertensionmentioning

confidence: 99%

Receptor Tyrosine Kinase Inhibitors in Rodent Pulmonary Hypertension

Moreno‐Vinasco

Garcia

2009

Advances in Experimental Medicine and Biology

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Pulmonary hypertension (PH) is a disorder characterized by vascular remodeling and proliferation, a phenotype dependent upon unimpeded growth factor and kinase pathway activation with strong similarities to malignant tumors. This chapter details our novel application of the multikinase inhibitor, sorafenib, in rodent models of PH to improved hemodynamic parameters and attenuates PH structural changes1. Sorafenib is a Raf kinase inhibitor and our biochemical and genomic evidence supported the potential involvement of the MAPK cascade system and TGFB3 in PH development and the response to therapy. Integration of expression genomic analyses coupled with intense bioinformatics identified gene expression and ontology signatures in the development of PH and implicated the role of cytoskeletal protein such as caldesmon or nmMLCK as potentially key participants in PH-induced vascular remodeling and proliferation. Our studies suggest the PKI sorafenib as a potentially novel treatment for severe PH with the MAPK cascade a potential canonical target profoundly effecting vascular cytoskeletal rearrangements and remodeling1.

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Microarray Analysis of Peripheral Blood Cells in Pulmonary Arterial Hypertension, Surrogate to Biopsy

Cited by 5 publications

References 0 publications

Transcriptional profiling of lymphoblast lines from subjects with panic disorder

Transcriptional profiling of lymphoblast lines from subjects with panic disorder

Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Receptor Tyrosine Kinase Inhibitors in Rodent Pulmonary Hypertension

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