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Adventitial alterations are the main features in pulmonary artery remodeling due to long-term chronic intermittent hypobaric hypoxia in rats.

ABSTRACT: Long-term chronic intermittent exposure to altitude hypoxia is a labor phenomenon requiring further research. Using a rat model, we examined whether this type of exposure differed from chronic exposure in terms of pulmonary artery remodeling and other features. Rats were subjected to chronic hypoxia (CH, n = 9) and long-term intermittent hypoxia (CIH2x2; 2 days of hypoxia/2 days of normoxia, n = 10) in a chamber (428 Torr, 4,600?m of altitude) for 46 days and compared to rats under normoxia (NX, n = 10). Body weight, hematocrit, and right ventricle ratio were measured. Pulmonary artery remodeling was assessed using confocal microscopy of tissues stained with a nuclear dye (DAPI) and CD11b antibody. Both hypoxic conditions exhibited increased hematocrit and hypertrophy of the right ventricle, tunica adventitia, and tunica media, with no changes in lumen size. The medial hypertrophy area (larger in CH) depicted a significant increase in smooth muscle cell number. Additionally, CIH2x2 increased the adventitial hypertrophy area, with an increased cellularity and a larger prevalence of clustered inflammatory cells. In conclusion, CIH2x2 elicits milder effects on pulmonary artery medial layer muscularization and subsequent right ventricular hypertrophy than CH. However, CIH2x2 induces greater and characteristic alterations of the adventitial layer.

SUBMITTER: Brito J

PROVIDER: S-EPMC4337174 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Adventitial alterations are the main features in pulmonary artery remodeling due to long-term chronic intermittent hypobaric hypoxia in rats.

Brito Julio J Siques Patricia P Arribas Silvia M SM López de Pablo Angel L AL González M Carmen MC Naveas Nelson N Arriaza Karem K Flores Karen K León-Velarde Fabiola F Pulido Ruth R Ordenes Stefany S López M Rosario MR

BioMed research international 20150208

Long-term chronic intermittent exposure to altitude hypoxia is a labor phenomenon requiring further research. Using a rat model, we examined whether this type of exposure differed from chronic exposure in terms of pulmonary artery remodeling and other features. Rats were subjected to chronic hypoxia (CH, n = 9) and long-term intermittent hypoxia (CIH2x2; 2 days of hypoxia/2 days of normoxia, n = 10) in a chamber (428 Torr, 4,600 m of altitude) for 46 days and compared to rats under normoxia (NX, ...[more]

PMID: 25738150

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Project description:Background: Moderate hypobaric hypoxia induces cerebral ischemic tolerance. We investigated the optimal method for applying hypobaric hypoxia preconditioning at 5,000 m to ischemic brain tissue and combined it with proteomics to determine the mechanisms underlying this effect. Methods: Male SD rats were randomly grouped as S (sham, n = 20), M (middle cerebral artery occlusion [MCAO], n = 28), H2M (intermittent hypobaric hypoxia preconditioned MCAO group, 2 h/day, 10 days, n = 20), H6M (intermittent hypobaric hypoxia preconditioned MCAO group, 6 h/day, 10 days, n = 28), and HpM (persistent hypobaric hypoxia preconditioned MCAO group, 10 days, n = 28). The permanent MCAO model was established based on the Zea Longa method. Infarction was assessed with the modified neurological severity score (mNSS) and 2,3,5-triphenyl tetrazolium chloride staining. The total protein expression of the neuron-specific nuclear protein (NeuN), cysteinyl aspartate specific proteinase 3 (caspase-3), cleaved-caspase-3, and interleukin 6 (IL-6) was determined using western blotting. We assessed the peri-infarct cortex's ultrastructural changes. A label-free proteomic study and western blot verification were performed on the most effective preconditioned group. Results: The H6M group showed a lower infarct volume (p = 0.0005), lower mNSS score (p = 0.0009) than the M group. The H2M showed a lower level of IL-6 (p = 0.0213) than the M group. The caspase-3 level decreased in the H2M (p = 0.0002), H6M (p = 0.0025), and HpM groups (p = 0.0054) compared with that in the M group. Cleaved-caspase-3 expression decreased in the H2M (p = 0.0011), H6M (p < 0.0001), and HpM groups (p < 0.0001) compared with that in the M group. The neurons' ultrastructure and the blood-brain barrier in the peri-infarct tissue improved in the H2M and H6M groups. Immunofluorescence revealed increased NeuN-positive cells in the peri-infarct tissue in the H6M group (p = 0.0003, H6M vs. M). Protein expression of Chmp1a, Arpc5, and Hspa2 factors related to endocytosis were upregulated in the H6M compared with those of the M group (p < 0.05 for all) on western blot verification of label-free proteomics. Conclusions: Intermittent hypobaric hypoxia preconditioning exerts a neuroprotective effect in a rat stroke model. Persistent hypobaric hypoxia stimulation exhibited no significant neuroprotective effect. Intermittent hypoxic preconditioning for 6 h/day for 10 days upregulates key proteins in clathrin-dependent endocytosis of neurons in the cortex.

Project description:Over the past 40 years, mining activities in Chile have relocated miners who normally live at sea level to work at high altitudes. This results in a form of chronic intermittent hypobaric hypoxia (CIHH) characterized by alternating periods of work at high altitude and rest periods at sea level. Previous studies performed in our laboratory showed that aerobic capacity is reduced at 3,800 m, even when oxygen content is maintained. Our study aimed to determine the corporal composition, food intake, maximum oxygen uptake, and concentration of high sensitivity C reactive protein (hsCRP) in an acclimatized miner population that work from 0 to 2,500 m with CIHH exposure over 4 years. All miners recruited for our study were operators of heavy trucks with CIHH for over 4 years (shiftwork 7*7 days), and our experimental population was composed of 54 miners at sea level, 61 at 1,600 m, and 38 at 2,500 m. All evaluations were performed on the 3rd or 4th day of diurnal shiftwork. To determine corporal composition, we measured weight and height (to calculate body mass index, BMI), skinfolds (to calculate body fatty, BF), and waist circumference (WC); maximal aerobic capacity was evaluated using a ramp-incremental cycling to exhaustion protocol and a venous blood sample before the exercise test to measure (hsCRP) via an ELISA test. We found higher values of BMI, BF, and WC, in the miners' population but observed no significant difference between populations. We found a decrease in VO2 of 11.6% at 1,600 m and 25.9% at 2,500 m compared to miners at sea level. An increase in (hsCRP) at 1,600 and 2,500 m regards sea level. We observed a high prevalence of overweight and obese subjects, which was related to the ad libitum availability of food and low physical activity (sedentarism). We found that work capacity was maintained despite a decreased VO2 max at moderate altitude. However, overweight and obesity support an increased risk of cardiometabolic disease in miner's which is unrelated to altitude. In contrast, an increased hsCRP level could be associated with increased inflammatory mechanisms at 1,600 and 2,500 m.

Project description:More than 140 million people live and works (in a chronic or intermittent form) above 2500 m worldwide and 35 million live in the Andean Mountains. Furthermore, in Chile, it is estimated that 55,000 persons work in high altitude shifts, where stays at lowlands and interspersed with working stays at highlands. Acute exposure to high altitude has been shown to induce oxidative stress in healthy human lowlanders, due to an increase in free radical formation and a decrease in antioxidant capacity. However, in animal models, intermittent hypoxia (IH) induce preconditioning, like responses and cardioprotection. Here, we aimed to describe in a rat model the responses on cardiac and vascular function to 4 cycles of intermittent hypobaric hypoxia (IHH). Twelve adult Wistar rats were randomly divided into two equal groups, a four-cycle of IHH, and a normobaric hypoxic control. Intermittent hypoxia was induced in a hypobaric chamber in four continuous cycles (1 cycle = 4 days hypoxia + 4 days normoxia), reaching a barometric pressure equivalent to 4600 m of altitude (428 Torr). At the end of the first and fourth cycle, cardiac structural, and functional variables were determined by echocardiography. Thereafter, ex vivo vascular function and biomechanical properties were determined in femoral arteries by wire myography. We further measured cardiac oxidative stress biomarkers (4-Hydroxy-nonenal, HNE; nytrotirosine, NT), reactive oxygen species (ROS) sources (NADPH and mitochondrial), and antioxidant enzymes activity (catalase, CAT; glutathione peroxidase, GPx, and superoxide dismutase, SOD). Our results show a higher ejection and shortening fraction of the left ventricle function by the end of the 4th cycle. Further, femoral vessels showed an improvement of vasodilator capacity and diminished stiffening. Cardiac tissue presented a higher expression of antioxidant enzymes and mitochondrial ROS formation in IHH, as compared with normobaric hypoxic controls. IHH exposure determines a preconditioning effect on the heart and femoral artery, both at structural and functional levels, associated with the induction of antioxidant defence mechanisms. However, mitochondrial ROS generation was increased in cardiac tissue. These findings suggest that initial states of IHH are beneficial for cardiovascular function and protection.

Dataset Information

Adventitial alterations are the main features in pulmonary artery remodeling due to long-term chronic intermittent hypobaric hypoxia in rats.

Publications

Adventitial alterations are the main features in pulmonary artery remodeling due to long-term chronic intermittent hypobaric hypoxia in rats.

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