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Item Acute Exercise Activates Pulmonary eNOS and Lowers Pulmonary Pressure in Rats with Pulmonary Arterial Hypertension(Office of the Vice Chancellor for Research, 2013-04-05) Chingombe, Tsungai J.; Reddy, Jag; Fisher, Amanda; Presson, Robert G.; Lahm, Tim; Petrache, Irina; Brown, Mary BethNO-dependent arterial relaxation is impaired in pulmonary arterial hypertension (PAH). Exercise may be beneficial in PAH, just as it is for systemic vascular disease, via upregulation of endothelial nitric oxide synthase (eNOS) expression and activity. However, exercise-induced cardiac stress in PAH could also promote detrimental RV inflammation. We investigated pulmonary pressure and eNOS, as well inflammatory indicators in the RV, following a single 45 min run bout at moderate intensity in a rat model of PAH. Male Sprague-Dawley rats received either monocrotaline to induce PAH, or saline, for healthy controls. A subset of PAH and healthy controls performed 4 wks of progressive TM familiarization (15-30min, 8-20 m/min) in preparation for their final 45 min run @ 75% of VO2max. Immediately following the run, RV systolic pressure was measured and RV and lung tissues were harvested and cryofixed. eNOS and phosphorylated (at Ser1177) eNOS (p-eNOS) was measured via immunoblotting in lung homogenates and expressed normalized to vinculin. Immunofluorescence for inflammatory markers CD45/68 in cryofixed RV sections evaluated the acute inflammatory response to exercise. MCT reduced VO2max and caused RV hypertrophy (expressed as RV/LV+septum) as consistent with this model. RVSP (normalized by systemic BP) was lower in PAH-Ex vs. unexercised PAH with no difference between exercised and unexercised controls. Greater p-eNOS was measured in PAH-Ex lung compared to unexercised PAH, with no difference between exercised and unexercised controls. PAH-Ex also tended to have greater pulmonary eNOS than their unexercised counterparts. No greater exercise-induced CD45/68 infiltration was observed in RV of PAH compared to that of controls. In rats with moderate MCT-induced PAH, a single exercise bout does not increase acute RV inflammation but lowers pulmonary pressure, possibly mediated in part via pulmonary eNOS activation.Item EFFECT OF TREADMILL RUNNING ON CARDIAC AND SKELETAL MUSCLE METABOLISM AND RIGHT VENTRICLE INFLAMMATION IN RATS WITH PULMONARY ARTERIAL HYPERTENSION(Office of the Vice Chancellor for Research, 2012-04-13) Chingombe, Tsungai J.; Lahm, Tim; Reddy, Jag; Fisher, Amanda; Petrache, Irina; Brown, Mary BethIt has been suggested that a shift from oxidative to non-oxidative (glycolytic) metabolism promotes a right ventricle (RV) and skeletal muscle dysfunction in patients with pulmonary arterial hypertension (PAH), contributing to their reduced exercise tolerance. Exercise training may ameliorate this glycolytic switch in PAH as it does for other cardiopulmonary diseases. However, whether exercise-induced cardiac stress also promotes detrimental RV inflammation in PAH has not yet been thoroughly examined. We hypothesized that exercise training will promote a shift back towards the more efficient oxidative metabolism in cardiac and skeletal muscle of PAH rats and that 45 minutes of exercise at a prescribed moderate intensity will not promote greater RV inflammation in PAH rats. Tissues were obtained from monocrotaline-induced PAH and healthy control rats immediately following a 45 min treadmill run (75% VO2max) that concluded a 4 week treadmill familiarization/running program (15-45 min, 4x/wk). A group of unexercised PAH and healthy rats served as sedentary controls. Immunofluorescent staining (IF) for inflammatory markers CD45 (lymphocytes) and CD68 (macrophages) in cryofixed RV sections were used to assess the acute inflammatory response to exercise. In fixed soleus and RV sections, IF for the glucose transporter Glut1, and for capillary marker CD31, were used as indicators of glycolytic metabolism and tissue capillarization, respectively. Data thus far indicates no greater acute exercise-induced RV inflammation in PAH rats compared to healthy rats. We observed higher expression of Glut1 and lower capillarization in the RV and soleus of PAH rats, indicative of a shift toward greater dependency on non-oxidative metabolism. However, since Glut1 levels for exercised rats were measured in tissue harvested immediately following a run bout, evaluation of a chronic training effect on Glut1 expression is potentially confounded by the acute exercise effect and therefore remains to be investigated in a follow-up study.Item Investigating Skeletal Muscle Metabolic Adaptations underlying Aerobic Fitness Gains following High Intensity Interval Training in a Rat Model of Pulmonary Arterial Hypertension(Office of the Vice Chancellor for Research, 2016-04-08) Talley, Mary; Troutman, Ashley; Neves, Evandro; Fisher, Amanda; Graber, Jeremy; Gladish, Brett; Presson, Robert; Petrache, Irina; Kline, Jeffrey A.; Lahm, TimRationale: In patients with pulmonary arterial hypertension (PAH) a shift from oxidative to a less efficient non-oxidative (glycolytic) metabolism in skeletal muscle is believed to contribute to the reduced exercise tolerance hallmark of the disease. As seen for other cardiopulmonary diseases, exercise training (ExT) may ameliorate this “glycolytic switch” in PAH and improve exercise capacity. Previous studies in this lab showed an improved metabolic profile of skeletal muscle in PAH rats following an ExT protocol of continuous running at moderate relative intensity, 60 minutes at 75% of maximal aerobic capacity (VO2 Max). This study tests the hypothesis in a PAH rat model that HIIT will also result in preserved aerobic capacity and attenuation of skeletal muscle glycolytic shift. Methods: Male Sprague-Dawley rats received either monocrotaline (MCT, 40 mg/kg) to induce mild PAH (n= 14), or saline, for healthy controls (n=9). After 2 wks, a 6 wkprogram of treadmill HIIT was initiated for a subset of PAH (n= 8) and healthy controls (n=6). The 30 min HIIT sessions alternated between 2 minutes at 85% VO2 max and 3 minutes at ~30% VO2 max. VO2 max was assessed at baseline, and in pre-training and post-training via analysis of expired gases. Preliminary results: MCT-induced decrement in VO2 max was attenuated by HIIT (p<0.05). Soleus muscle hypertrophy (soleus mass relative to body mass) tended to be higher (p=0.07) in HIIT vs. SED MCT. Membrane glucose transporter Glut-1, a marker of glycolytic metabolism, was evaluated in soleus cryosections with immunofluorescent staining and abundance was similar between sedentary and HIIT MCT rats (p>0.05). Western blotting of soleus homogenates for cytochromes I-V of the electron transport chain (OXPHOS), and for PGC1α, a potent stimulus for mitochondrial biogenesis, is being performed at present to further investigate potential training-induced adaptations in skeletal muscle metabolismItem Investigating Skeletal Muscle Metabolic Adaptations underlying Aerobic Fitness Gains Following High Intensity Interval Training in a Rat Model of Pulmonary Arterial Hypertension(Office of the Vice Chancellor for Research, 2015-04-17) Talley, Mary; Novack, Rachel; Chingombe, Tsungai J.; Lahm, Tim; Petrache, Irina; Brown, Mary BethRationale: In patients with pulmonary arterial hypertension (PAH) a shift from oxidative to a less efficient non-oxidative (glycolytic) metabolism in skeletal muscle is believed to contribute to the reduced exercise tolerance hallmark of the disease. As seen for other cardiopulmonary diseases, exercise training (ExT) may ameliorate this “glycolytic switch” in PAH and improve exercise capacity. Previous studies in this lab showed an improved metabolic profile of skeletal muscle in PAH rats following an ExT protocol of continuous running at moderate relative intensity, 60 minutes at 75% of maximal aerobic capacity (VO2Max). High intensity interval training (HIIT) has been shown in healthy individuals as well as in patients with cardiovascular disease to promote favorable cardiac and skeletal muscle adaptations and greater improvements in aerobic capacity versus customary continuous training. This study tests the hypothesis in a PAH rat model that HIIT will result in preserved aerobic capacity and a greater attenuation of skeletal muscle glycolytic shift than that observed with continuous moderate intensity exercise. Methods: Male Sprague-Dawley rats received either monocrotaline (MCT, 40 mg/kg, s.q.) to induce PAH (n= 8), or saline, for healthy controls (n=4). After 2 wks, with MCT-induced PAH wellestablished, 6 wks of treadmill HIIT was initiated for a subset of PAH animals (PAH-ExT, n= 6) and healthy controls (CON-ExT, n=2). The HIIT runs were alternated between 2 to 3 minutes of high intensity exercise (85% VO2max reserve) and active recovery intervals between 2 to 3 minutes (10 m/min, 0 incline) VO2max was assessed at baseline, and in pre-training and post-training via analysis of expired gases during incremental treadmill running. Preliminary results: MCT-induced decrement in VO2max was attenuated by HIIT. Abundance of membrane glucose transporter Glut-1, a marker of glycolytic metabolism, is currently being evaluated in soleus cryosections with immunofluorescent staining. Findings are being compared to historical data for PAH and healthy rats from a study protocol that differed only by training approach-continuous instead of HIIT.