Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Genomic alterations during the progress of pulmonary hypertension

ABSTRACT: Pulmonary hypertension (PH), a rare disorder is a complication of a number of cardiopulmonary, unrelated systemic diseases, drug toxicity and genetic mutations. Major advances have been made in the field, but the pathogenesis of PH is not yet understood. Several experimental models such as monocrotaline (MCT) and hypoxia have been used to understand the mechanism underlying the pathogenesis of PH. We have recently shown that that the addition of hypoxia to MCT injected rats accelerates the disease process leading to neointima formation. We have profiled the lungs of adult male Sprague-Dawley rats kept for 4 weeks in normal atmospheric conditions or in hypobaric hypoxia (380 mmHg) w/o subcutaneous injection with 40 mg/kg MCT or just saline. While MCT and hypoxia altered expression of few genes when applied separately, together they induced a substantial alteration of the transcriptome. The most profoundly altered pathways by the combined effect of hypoxia and MCT were: endocytosis, apoptosis, HIF-1 signaling pathway and vascular smooth muscle contraction. Two-condition (C = normal atmospheric conditions (control) vs H = hypobaric hypoxia) + two treatment (M = with MCT, O = without MCT) experiment. Four biological replicas of each combination: CO, HO, CM, HM. Differently labeled biological replicates were cohybridized with each array. Results of similarly labeled different conditions were compared then averaged for the two fluorescent labels. For instance: CO1 & CO3 were compared with CM1 & CM3, CO2 & CO4 were compared with CM2 & + CM4, and the results of the comparisons averaged. This design uses 100% of the resources, has a better normlaiztion and allows all possible comparisons among the conditions.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Dumitru Iacobas

PROVIDER: E-GEOD-72707 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In order to understand the chronic hypoxia (CH) effect upon the absence of dystrophin, Drosophila melanogaster wild type and the model for DMD (dmDys), in which all dystrophins expression was knocked out by iRNA, were exposed to high altitude hypoxia (hypobaric hypoxia) during a 16-day climbing period reaching the summit of Mount McKinley (6194 meters above sea level). Furthermore, dmDys and Drosophila wild type were exposed to normobaric hypoxia (hypoxic chamber) following the same oxygen levels observed during the climbing expedition and to normoxic conditions for comparison. Affymetrix GeneChip¬Æ profiling was performed for individual flies from each experimental group. CH-dmDys differentially expressed 1281 genes, whereas control group differentially expressed 57 genes. Eight heat shock protein genes detected in the CH-dmDys microarray study were down-regulated, instead of up-regulated as seen in wild type hypoxic flies. This result suggests a differential gene expression response to CH, which could affect muscle performance.These results suggest that dmDys is more sensitive to CH due to reduced muscle function and hypoxic stress response. In order to understand the chronic hypoxia (CH) effect upon the absence of dystrophin, Drosophila melanogaster wild type and the model for DMD (dmDys), in which all dystrophins expression was knocked out by iRNA, were exposed to high altitude hypoxia (hypobaric hypoxia) during a 16-day climbing period reaching the summit of Mount McKinley (6194 meters above sea level). Furthermore, dmDys and Drosophila wild type were exposed to normobaric hypoxia (hypoxic chamber) following the same oxygen levels observed during the climbing expedition and to normoxic conditions for comparison. Affymetrix GeneChip¬Æ profiling was performed for individual flies from each experimental group. CH-dmDys differentially expressed 1281 genes, whereas control group differentially expressed 57 genes. Eight heat shock protein genes detected in the CH-dmDys microarray study were down-regulated, instead of up-regulated as seen in wild type hypoxic flies. This result suggests a differential gene expression response to CH, which could affect muscle performance.These results suggest that dmDys is more sensitive to CH due to reduced muscle function and hypoxic stress response. Overall design: Adults wild type and dystrophic flies (3-5 days old) were exposed to hypobaric hypoxia for two weeks during the summer expedition to Mount McKinley, Alaska (6194 MASL). Another set of wild types and dystrophic flies were exposed to normobaric hypoxia according to the table I obtained during the climbing expedition. During the expedition, the flies were maintained in vials with regular molasses and covered by thermo isolation to avoid low temperature, keeping the temperature at 25C. The experiment performed in the laboratory also used vials with regular molasses and at 25C. Table I. Expedition log book for mount McKinley ascent. Information obtained during the ascent and summit of Mount McKinley, June 1st to June 16th of 2007. The oxygen pressure (PO2) was calculated from the barometric pressure. GNB means go and back from the mentioned point. DAY In order to understand the chronic hypoxia (CH) effect upon the absence of dystrophin, Drosophila melanogaster wild type and the model for DMD (dmDys), in which all dystrophins expression was knocked out by iRNA, were exposed to high altitude hypoxia (hypobaric hypoxia) during a 16-day climbing period reaching the summit of Mount McKinley (6194 meters above sea level). Furthermore, dmDys and Drosophila wild type were exposed to normobaric hypoxia (hypoxic chamber) following the same oxygen levels observed during the climbing expedition and to normoxic conditions for comparison. Affymetrix GeneChip¬Æ profiling was performed for individual flies from each experimental group. CH-dmDys differentially expressed 1281 genes, whereas control group differentially expressed 57 genes. Eight heat shock protein genes detected in the CH-dmDys microarray study were down-regulated, instead of up-regulated as seen in wild type hypoxic flies. This result suggests a differential gene expression response to CH, which could affect muscle performance.These results suggest that dmDys is more sensitive to CH due to reduced muscle function and hypoxic stress response. In order to understand the chronic hypoxia (CH) effect upon the absence of dystrophin, Drosophila melanogaster wild type and the model for DMD (dmDys), in which all dystrophins expression was knocked out by iRNA, were exposed to high altitude hypoxia (hypobaric hypoxia) during a 16-day climbing period reaching the summit of Mount McKinley (6194 meters above sea level). Furthermore, dmDys and Drosophila wild type were exposed to normobaric hypoxia (hypoxic chamber) following the same oxygen levels observed during the climbing expedition and to normoxic conditions for comparison. Affymetrix GeneChip¬Æ profiling was performed for individual flies from each experimental group. CH-dmDys differentially expressed 1281 genes, whereas control group differentially expressed 57 genes. Eight heat shock protein genes detected in the CH-dmDys microarray study were down-regulated, instead of up-regulated as seen in wild type hypoxic flies. This result suggests a differential gene expression response to CH, which could affect muscle performance.These results suggest that dmDys is more sensitive to CH due to reduced muscle function and hypoxic stress response. Overall design: Adults wild type and dystrophic flies (3-5 days old) were exposed to hypobaric hypoxia for two weeks during the summer expedition to Mount McKinley, Alaska (6194 MASL). Another set of wild types and dystrophic flies were exposed to normobaric hypoxia according to the table I obtained during the climbing expedition. During the expedition, the flies were maintained in vials with regular molasses and covered by thermo isolation to avoid low temperature, keeping the temperature at 25C. The experiment performed in the laboratory also used vials with regular molasses and at 25C. Table I. Expedition log book for mount McKinley ascent. Information obtained during the ascent and summit of Mount McKinley, June 1st to June 16th of 2007. The oxygen pressure (PO2) was calculated from the barometric pressure. GNB means go and back from the mentioned point. DAY LOCATION ALTITUDE m PO2 mmHg (%) 1 Base Camp 2200 123.6 (16.3%) 2 Base Camp 2200 123.6 (16.3%) 3 Base Camp 2200 123.6 (16.3%) 4 Ski Hill 2400 120.7 (15.9%) 5 Kahiltna Pass 2950 113.0 (14.9%) 6 Motorcycle Hill 3350 107.7 (14.2%) 7 Motorcycle Hill 3350 107.7 (14.2%) 8 GNB from Motorcycle 4150 (5 hours) 97.7 (12.9%) 9 Medical Camp 4350 95.3 (12.5%) 10 GNB from Medical Camp 4150 (5 hours) 97.7 (12.9%) 11 Medical Camp 4350 95.3 (12.5%) 12 GNB from Medical Camp 4900 89.0 (11.7%) 13 Medical Camp 4350 95.3 (12.5%) 14 High Camp 5250 85.1 (11.2%) 15 Summit 6194 (0.3 hours) 75.4 (9.9%) 16 High Camp 5250 85.1 (11.2%)

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Genomic alterations during the progress of pulmonary hypertension

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