Browsing by Subject "pulmonary arterial hypertension"
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Item Effects of aerobic exercise training on diaphragm muscle metabolism in a rat model of Pulmonary Arterial Hypertension(Office of the Vice Chancellor for Research, 2014-04-11) Pittman, Angela DPulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance that leads to right ventricular (RV) overload and eventually RV failure and death. PAH is associated with diaphragm muscle dysfunction and increased work of breathing which contributes to the exercise intolerance that is hallmark in this patient population. Our lab and others have described a shift in substrate utilization toward non-oxidative (glycolytic) metabolism in the RV and skeletal muscle of PAH rodent models as well as in patients. This project will determine if ‘glycolytic shift’ also occurs in the diaphragm muscle which may contribute to exercise intolerance and dyspnea. Since regular aerobic exercise is well-known to promote adaptations enhancing oxidative metabolism in cardiac muscle and skeletal muscle of the extremities, this project will also investigate the impact of exercise training on diaphragm muscle metabolism. Diaphragm muscles were harvested upon completion of a 6 week, 4x/wk. treadmill training program that consisted of 60 min runs at a relative intensity of 50% of aerobic capacity (VO2max). Abundance of glucose transporter Glut-1, a marker of glycolytic metabolism, is being evaluated by Immunoflourescent (IF) staining at the cell membrane of diaphragm myocytes. We expect to find that PAH rats have greater abundance of diaphragm Glut-1 and that exercise training at least partially ameliorates this PAH-induced ‘glycolytic shift’.Item Exercise Training Improves Cardiac and Skeletal Muscle Metabolism in Rats with Pulmonary Arterial Hypertension(Office of the Vice Chancellor for Research, 2013-04-05) Gaidoo, Richard G.; Crist, Jacob; Little, Nathaniel; Chingombe, Tsungai J.; Fisher, Amanda; Presson, Robert G.; Lahm, Tim; Petrache, Irina; Brown, Mary BethIn patients with pulmonary arterial hypertension (PAH), a shift from oxidative to glycolytic metabolism promotes right ventricular (RV) and skeletal muscle dysfunction that contributes to reduced exercise tolerance. As seen for other cardiopulmonary diseases, exercise training (ExT) may ameliorate this glycolytic switch in PAH and improve exercise capacity. The purpose of this research is to investigate ExT in a rat model of PAH on markers of glycolytic and oxidative metabolism in RV and skeletal muscle. Male Sprague-Dawley rats received monocrotaline (MCT, 40 mg/kg, s.q.) to induce PAH (n= 13), or saline, for healthy controls (n=5). After 2 wks, with MCT-induced PAH established, 6 wks of treadmill (TM) ExT was initiated for a subset of PAH animals (PAH-ExT, n= 6) and healthy controls (CON-ExT, n=3). ExT runs progressed up to 60 min at mild relative intensity, 50% of maximal aerobic capacity (VO2max). VO2max was assessed at baseline, in pre-training and post-training TM testing via analysis of expired gases. Abundance of Glut-1, a marker of glycolytic metabolism, was evaluated in cryosections of RV and soleus with immunofluorescent (IF) staining and quantification. Data are presented as mean±SE. MCT-ExT rats maintained aerobic capacity over 6 wks better than sedentary counterparts (MCT-SED)(VO2max= -134±109 vs. -521±129 ml/kg/hr, p=0.04) and was not different than CON-ExT (-201±31 ml/kg/hr, p=0.82). A lower abundance of Glut-1 was observed in both RV and soleus myocytes of PAH-ExT rats (MPI= 10.9 ±0.9 for RV; 13.7±0.8 for soleus) compared to PAH-SED rats (15.7±2.4, p=0.05, for RV; 17.4±1.4, p=0.04, for soleus) and was similar to CON-ExT rats (13.0±2.2, p=0.33, for RV; 9.0±2.3, p=0.26, for soleus), indicative of a shift toward greater dependency on oxidative metabolism. Exercise training attenuates functional decline following MCT administration in rats. Preservation of aerobic capacity may be explained by promotion of more efficient RV and skeletal muscle mitochondrial substrate utilization.Item Pulmonary-arterial-hypertension (PAH)-on-a-chip: fabrication, validation and application(The Royal Society of Chemistry, 2020-07-28) Al-Hilal, Taslim A.; Keshavarz, Ali; Kadry, Hossam; Lahooti, Behnaz; Al-Obaida, Ahmed; Ding, Zhenya; Li, Wei; Kamm, Roger; McMurtry, Ivan F.; Lahm, Tim; Nozik-Grayck, Eva; Stenmark, Kurt R.; Ahsan, Fakhrul; Anatomy and Cell Biology, School of MedicineCurrently used animal and cellular models for pulmonary arterial hypertension (PAH) only partially recapitulate its pathophysiology in humans and are thus inadequate in reproducing the hallmarks of the disease, inconsistent in portraying the sex-disparity, and unyielding to combinatorial study designs. Here we sought to deploy the ingenuity of microengineering in developing and validating a tissue chip model for human PAH. We designed and fabricated a microfluidic device to emulate the luminal, intimal, medial, adventitial, and perivascular layers of a pulmonary artery. By growing three types of pulmonary arterial cells (PACs)-endothelial, smooth muscle, and adventitial cells, we recreated the PAH pathophysiology on the device. Diseased (PAH) PACs, when grown on the chips, moved of out their designated layers and created phenomena similar to the major pathologies of human PAH: intimal thickening, muscularization, and arterial remodeling and show an endothelial to mesenchymal transition. Flow-induced stress caused control cells, grown on the chips, to undergo morphological changes and elicit arterial remodeling. Our data also suggest that the newly developed chips can be used to elucidate the sex disparity in PAH and to study the therapeutic efficacy of existing and investigational anti-PAH drugs. We believe this miniaturized device can be deployed for testing various prevailing and new hypotheses regarding the pathobiology and drug therapy in human PAH.Item Systems Analysis of the Human Pulmonary Arterial Hypertension Lung Transcriptome(American Thoracic Society, 2018-11-09) Stearman, Robert S.; Bui, Quan M.; Speyer, Gil; Handen, Adam; Cornelius, Amber R.; Graham, Brian B.; Kim, Seungchan; Mickler, Elizabeth A.; Tuder, Rubin M.; Chan, Stephen Y.; Geraci, Mark W.; Medicine, School of MedicinePulmonary arterial hypertension (PAH) is characterized by increased pulmonary artery pressure and vascular resistance, typically leading to right heart failure and death. Current therapies improve quality of life of the patients but have a modest effect on long-term survival. A detailed transcriptomics and systems biology view of the PAH lung is expected to provide new testable hypotheses for exploring novel treatments. We completed transcriptomics analysis of PAH and control lung tissue to develop disease-specific and clinical data/tissue pathology gene expression classifiers from expression datasets. Gene expression data were integrated into pathway analyses. Gene expression microarray data were collected from 58 PAH and 25 control lung tissues. The strength of the dataset and its derived disease classifier was validated using multiple approaches. Pathways and upstream regulators analyses was completed with standard and novel graphical approaches. The PAH lung dataset identified expression patterns specific to PAH subtypes, clinical parameters, and lung pathology variables. Pathway analyses indicate the important global role of TNF and transforming growth factor signaling pathways. In addition, novel upstream regulators and insight into the cellular and innate immune responses driving PAH were identified. Finally, WNT-signaling pathways may be a major determinant underlying the observed sex differences in PAH. This study provides a transcriptional framework for the PAH-diseased lung, supported by previously reported findings, and will be a valuable resource to the PAH research community. Our investigation revealed novel potential targets and pathways amenable to further study in a variety of experimental systems.