Effects of zinc on the right cardiovascular circuit in long-term hypobaric hypoxia in wistar rats

Hypobaric hypoxia under chromic conditions triggers hypoxic pulmonary vasoconstriction (HPV) and right ventricular hypertrophy (RVH). The role of zinc (Zn) under hypoxia is controversial and remains unclear. We evaluated the effect of Zn supplementation in prolonged hypobaric hypoxia on HIF2α/MTF-1/MT/ZIP12/PKCε pathway in the lung and RVH. Wistar rats were exposed to hypobaric hypoxia for 30 days and randomly allocated into three groups: chronic hypoxia (CH); intermittent hypoxia (2 days hypoxia/2 days normoxia; CIH); and normoxia (sea level control; NX). Each group was subdivided (n = 8) to receive either 1% Zn sulfate solution (z) or saline (s) intraperitoneally. Body weight, hemoglobin, and RVH were measured. Zn levels were evaluated in plasma and lung tissue. Additionally, the lipid peroxidation levels, HIF2α/MTF-1/MT/ZIP12/PKCε protein expression and pulmonary artery remodeling were measured in the lung. The CIH and CH groups showed decreased plasma Zn and body weight and increased hemoglobin, RVH, and vascular remodeling; the CH group also showed increased lipid peroxidation. Zn administration under hypobaric hypoxia upregulated the HIF2α/MTF-1/MT/ZIP12/PKCε pathway and increased RVH in the intermittent zinc group. Under intermittent hypobaric hypoxia, Zn dysregulation could participate in RVH development through alterations in the pulmonary HIF2α/MTF1/MT/ZIP12/PKCε pathwa

Lower body weight in rats under hypobaric hypoxia exposure would lead to reduced right ventricular hypertrophy and Increased AMPK activation

Background: Both chronic hypoxia (CH) and long-term chronic intermittent hypoxia (CIH) exposure lead to right ventricular hypertrophy (RVH). Weight loss is an effective intervention to improve cardiac function and energy metabolism in cardiac hypertrophy. Likewise, caloric restriction (CR) also plays an important role in this cardioprotection through AMPK activation. We aimed to determine the influence of body weight (BW) on RVH, AMPK and related variables by comparing rats exposed to both hypoxic conditions. Methods: Sixty male adult rats were separated into two groups (n = 30 per group) according to their previous diet: a caloric restriction (CR) group and an ad libitum (AL) group. Rats in both groups were randomly assigned to 3 groups: a normoxic group (NX, n = 10), a CIH group (2 days hypoxia/2 days normoxia; n = 10) and a CH group (n = 10). The CR group was previously fed 10 g daily, and the other was fed ad libitum. Rats were exposed to simulated hypobaric hypoxia in a hypobaric chamber set to 428 Torr (the equivalent pressure to that at an altitude of 4,600 m above sea level) for 30 days. Measurements included body weight; hematocrit; serum insulin; glycemia; the degree of RVH (Fulton’s index and histology); and AMPK, mTOR, and PP2C expression levels in the right ventricle determined by western blotting. Results: A lower degree of RVH, higher AMPK activation, and no activation of mTOR were found in the CR groups exposed to hypobaric hypoxia compared to the AL groups (p < 0.05). Additionally, decreased glycemia and serum insulin levels were observed. Interestingly, PP2C expression showed an increase in the AL groups but not in the CR groups (p < 0.05). Conclusion: Maintaining a low weight before and during exposure to high-altitude hypoxia, during either CH or CIH, could prevent a major degree of RVH. This cardioprotection would likely be due to the activation of AMPK. Thus, body weight is a factor that might contribute to RVH at high altitudes.This study was supported by grants from projects GORE FIC Tarapacá BIP30477541-0 and Internal Project VRIIP0098

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

Long-termchronic 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, = 9) and long-term intermittent hypoxia (CIH2x2; 2 days of hypoxia/2 days of normoxia, = 10) in a chamber (428 Torr, 4,600m of altitude) for 46 days and compared to rats under normoxia (NX, = 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 elicitsmilder effects on pulmonary artery medial layermuscularization and subsequent right ventricular hypertrophy than CH. However, CIH2x2 induces greater and characteristic alterations of the adventitial layerThis work was funded by GORE-FNDR-BIP: 30125349-0, AECID Nº A/030023/10, and CYTED-ALTMEDFIS grant

Long-Term Chronic Intermittent Hypobaric Hypoxia Induces Glucose Transporter (GLUT4) Translocation Through AMP-Activated Protein Kinase (AMPK) in the Soleus Muscle in Lean Rats

Background: In chronic hypoxia (CH) and short-term chronic intermittent hypoxia (CIH) exposure, glycemia and insulin levels decrease and insulin sensitivity increases, which can be explained by changes in glucose transport at skeletal muscles involving GLUT1, GLUT4, Akt, and AMPK, as well as GLUT4 translocation to cell membranes. However, during long-term CIH, there is no information regarding whether these changes occur similarly or differently than in other types of hypoxia exposure. This study evaluated the levels of AMPK and Akt and the location of GLUT4 in the soleus muscles of lean rats exposed to long-term CIH, CH, and normoxia (NX) and compared the findings.Methods: Thirty male adult rats were randomly assigned to three groups: a NX (760 Torr) group (n = 10), a CIH group (2 days hypoxia/2 days NX; n = 10) and a CH group (n = 10). Rats were exposed to hypoxia for 30 days in a hypobaric chamber set at 428 Torr (4,600 m). Feeding (10 g daily) and fasting times were accurately controlled. Measurements included food intake (every 4 days), weight, hematocrit, hemoglobin, glycemia, serum insulin (by ELISA), and insulin sensitivity at days 0 and 30. GLUT1, GLUT4, AMPK levels and Akt activation in rat soleus muscles were determined by western blot. GLUT4 translocation was measured with confocal microscopy at day 30.Results: (1) Weight loss and increases in hematocrit and hemoglobin were found in both hypoxic groups (p < 0.05). (2) A moderate decrease in glycemia and plasma insulin was found. (3) Insulin sensitivity was greater in the CIH group (p < 0.05). (4) There were no changes in GLUT1, GLUT4 levels or in Akt activation. (5) The level of activated AMPK was increased only in the CIH group (p < 0.05). (6) Increased GLUT4 translocation to the plasma membrane of soleus muscle cells was observed in the CIH group (p < 0.05).Conclusion: In lean rats experiencing long-term CIH, glycemia and insulin levels decrease and insulin sensitivity increases. Interestingly, there is no increase of GLUT1 or GLUT4 levels or in Akt activation. Therefore, cellular regulation of glucose seems to primarily involve GLUT4 translocation to the cell membrane in response to hypoxia-mediated AMPK activation

The Long-Term Pannexin 1 Ablation Produces Structural and Functional Modifications in Hippocampal Neurons

Enhanced activity and overexpression of Pannexin 1 (Panx1) channels contribute to neuronal pathologies such as epilepsy and Alzheimer’s disease (AD). The Panx1 channel ablation alters the hippocampus’s glutamatergic neurotransmission, synaptic plasticity, and memory flexibility. Nevertheless, Panx1-knockout (Panx1-KO) mice still retain the ability to learn, suggesting that compensatory mechanisms stabilize their neuronal activity. Here, we show that the absence of Panx1 in the adult brain promotes a series of structural and functional modifications in the Panx1-KO hippocampal synapses, preserving spontaneous activity. Compared to the wild-type (WT) condition, the adult hippocampal neurons of Panx1-KO mice exhibit enhanced excitability, a more complex dendritic branching, enhanced spine maturation, and an increased proportion of multiple synaptic contacts. These modifications seem to rely on the actin–cytoskeleton dynamics as an increase in the actin polymerization and an imbalance between the Rac1 and the RhoA GTPase activities were observed in Panx1-KO brain tissues. Our findings highlight a novel interaction between Panx1 channels, actin, and Rho GTPases, which appear to be relevant for synapse stability