Chronic Hypoxia Group Research Articles

Study on the mechanism of echinacoside in preventing and treating hypoxic pulmonary hypertension based on proteomic analyses.

Hypoxic pulmonary hypertension (HPH), a chronic condition affecting the cardiopulmonary system, has high mortality. Echinacoside (ECH) is a phenylethanoid glycoside, which is used to ameliorate pulmonary vascular remodeling and pulmonary vasoconstriction in rats. Accordingly, we aimed to explore the mechanism of ECH in preventing and treating HPH. Sprague Dawley rats were housed in a hypobaric hypoxia chamber for 28 days to obtain the HPH model. The experimental rats were randomly allocated into the following several groups: normoxia group, chronic hypoxia group, and ECH group. The therapeutic results of ECH (10, 20, and 40 mg/kg) showed that ECH reduced mPAP, Hb, Hct, and RVHI in HPH rats. Then this work employed label-free quantitative proteomic analysis, western blotting, and RT-PCR to investigate the mechanism by which ECH prevents HPH. The results found that in the chronic hypoxia group, the levels of ACSL1, COL6A1, COL4A2, COL1A1, and PC increased compared to the normoxia group. However, the opposite effect was observed in the chronic hypoxia group treated with ECH. The study indicates that the administration of ECH may slow the pathological progression of HPH by suppressing the inflammatory response, inhibiting smooth muscle cell proliferation, and minimizing the deposition of extracellular matrix.

The Influence of Experimental Chronic Antenatal and Acute Postnatal Hypoxia on the Morphological State of the Liver Stromal Component

BACKGROUND: At present, the asymptomatic course of liver pathology in early childhood remains an urgent problem. AIMS: The objective of the study was the detection of morphological features of the stromal component of the liver of rats, which were at different stages of postnatal ontogenesis and were exposed to chronic antenatal and acute postnatal hypoxia (APH). MATERIALS AND METHODS: The study material was rat liver tissue of the control group, the APH group, and the chronic antenatal hypoxia (CAH) group. RESULTS: From day 1 to day 35, CAH leads to an increase and growth of the stromal component in the liver of offsprings due to the development of sclerotic changes caused by activation of collagen formation with a predominance of mature collagen Type I over immature collagen Type III on day 1 and day 14 of the experiment and predominance of collagen Type III over collagen Type I on day 35 of the experiment, increasing the expression of fibronectin. Starting from day 14, APH leads to the development of sclerotic changes in this organ which increase to day 35, less pronounced compared to the detected sclerotic changes in CAH, and manifest in increased expression of fibronectin, activation of collagen formation with a predominance of collagen Type I over collagen Type III on days 14 and 35 of the experiment. CONCLUSION: CAH from day 1 and APH from day 14 of postnatal life lead to the development of sclerotic changes in the liver of offsprings, which are more pronounced in cases of simulation of CAH and increase with age.

The Effect of HIF1-α/NF-κB/MMP2 Signaling Pathways Mediated by ALDH2 on Chronic Intermittent Hypoxia Induced Myocardial Injury in Rats

(1) Objective: To investigate the effect of HIF1-α/NF-κB/MMP2 signaling pathways mediated by ALDH2 on chronic intermittent hypoxia induced myocardial injury in rats. (2) Methods: Thirty SD rats were randomly assigned to three groups (10 rats in each group): control group (CONTROL), chronic intermittent hypoxia group (CIH), and CIH + ALDH2 group. Rats in the CIH + ALDH2 group were established by an intraperitoneal injection of the ALDH2 activator, Alda-1 (20 mg/kg), once a day for three consecutive days. After three months, changes in ventricular function were determined by ultrasound. The expressions of HIF1-α, NF-κB, and MMP2 proteins were detected by protein blotting, and the concentration of 4-HNE in myocardial tissue was measured. (3) Results: Compared with the control group, echocardiography showed that rats in the CIH group had significantly reduced myocardial function, elevated protein levels of HIF1-α, NF-κB, and MMP2 in myocardial tissues, and increased the expression of 4-HNE in myocardial tissues (P<0.01); Compared with the CIH group, rats in the CIH + ALDH2 group showed significant improvement in myocardial function, decreased protein levels of HIF1-α, NF-κB, and MMP2 in myocardial tissue, and decreased the expression of 4-HNE in myocardial tissue (P<0.01). (4) Conclusion: Chronic intermittent hypoxia increases the expression of HIF1-α to damage the myocardium and affect cardiac function, and ALDH2 inhibits the expression of HIF1-α to protect the myocardium.

Transcriptional Profiling in the Intestinal of Rats under Hypobaric Hypoxia

High-altitude ascent induces various physiological changes, with Gastrointestinal (GI) disorders being a prevalent occurrence. The gut plays a pivotal role in maintaining overall body homeostasis during normal physiological adaptation. The molecular and pathophysiological mechanisms underlying gastrointestinal injury resulting from exposure to a hypoxic environment remain largely unknown. To comprehensively explore the potential physiological changes associated with intestinal disorders after exposure to a hypobaric hypoxic environment, we employed genome-wide transcriptional profiling to examine gene expression alterations in the small intestine of rats. Our study involved RNA-Sequencing (RNA-Seq) of the intestinal tissues of rats exposed to simulated hypobaric hypoxia for 2 weeks (W2Z) and 4 weeks (W4Z), allowing us to investigate the transcriptional profile during both acute and chronic hypobaric hypoxic conditions in this animal model. We identified differentially expressed genes among the three groups. A principal component analysis revealed substantial distinctions between the acute and chronic hypobaric hypoxia groups when compared to the control group. Furthermore, pathway analysis indicated that the differentially expressed genes were associated with the interaction of neuroactive ligands and receptors. This suggests that the adaptation of rats to hypobaric hypoxia involves, at least partially, the regulation of the neuroactive ligand-receptor interaction pathway.

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 pathway.

Contrast Enhanced Ultrasonography of Kidney in Chronic Intermittent Hypoxia Rat Model.

The objective of our study was to assess the ability of contrast-enhanced ultrasound (CEUS) in evaluating renal microperfusion in an animal model. Twenty Sprague-Dawley rats were subdivided into two groups: the normal and chronic intermittent hypoxia (CIH) groups. In the CIH model, 10 Sprague-Dawley rats were exposed to CIH for 8 weeks to mimic obstructive sleep apnea (OSA). The CEUS parameters of the renal cortex and medulla were obtained and compared between groups. The pathological changes of the kidney tissues were examined by histological staining such as hematoxylin and eosin (H&E) and Masson's trichrome. CIH caused morphological damage to kidneys. In the cortex, the peak intensity (PI) (P=.009) was significantly lower and time to peak (Ttop) (P=.019) was significantly prolonged in the CIH group compared with the controls. The area under ascending curve (WiAUC) in the medulla and cortex were both significantly lower in the CIH group than those in the control group (P both <.05). CEUS parameters (including PI and WiAUC of the cortex and WiAUC of the medulla) were negatively correlated with serum creatinine (P all <.05). In the medulla, the area under descending curve (WoAUC) was positively correlated with serum creatinine (P=.027), PI was negatively correlated with uric acid (P=.034). CEUS parameters (including Ttop, PI, WoAUC, and WiAUC) reflect renal microvascular changes in CIH. CEUS could be a safe and accurate imaging method to assess renal microvascular damage in CIH rats.

Effects of NLRP3/Caspase-1 pathway on Banxia Houpu decoction in the intervention of chronic intermittent hypoxia in mice with renal inflammatory injury

Objective: To investigate the effects of Banxia Houpo decoction on the renal NLRP3/Caspase-1/IL-1β signaling pathway in chronic intermittent hypoxia mice. Methods: C57BL/6 mice were randomly divided into 3 groups, normal control group (Control), chronic intermittent hypoxia group (CIH), and Banxia Houpo decoction treatment group (BHD), with 10 mice in each group. Mice in the CIH group and BHD group were placed in a hypoxic chamber. The oxygen volume fraction in the cabin was decreased from 21% to 9% in 90 s, and then oxygen was filled in 90 s to gradually increase the oxygen volume fraction in the cabin to 21%, while the mice in the control group were placed in the cabin and filled with normal air, processing 8 hours per day for 21 days. The mice in BHD group were treated with Banxia Houpu decoction by gavage before entering the cabin every day, and the control group and CIH group were given an equal volume of normal saline. After modeling, the changes of renal function indexes in each group were detected; HE and Masson staining were used to observe the pathological conditions of the kidney; Western blot and immunohistochemical staining were used to detect the protein expression levels of the nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3), aspartate-specific cysteine protein 1(Caspase-1) and interleukine-1beta(IL-1β). Results: Compared with control group, the contents of serum renal functional indexes UA, BUN and SCr in CIH group were increased significantly (P<0.01), and after BHD treatment, they all were decreased significantly compared with CIH group (P<0.01). Compared with control group, the results of HE staining showed that in the CIH group, glomerular endothelial cells were degenerated and necrotic, and vacuoles of different sizes appeared in renal tubular epithelial cells, and a small amount of renal tubular epithelial cells fell off and died. The pathological condition of the BHD group was improved compared with CIH group, the glomerular morphology gradually returned to normal, and a small amount of renal tubular epithelial cells fell off and died. Compared with control group, Masson staining results showed that there was obvious fibrosis around the glomeruli in the CIH group, the fibrosis was significantly reduced in the BHD group. The expression levels of NLRP3, Caspase-1, IL-1β and IL-18 were increased significantly compared with control group (P<0.05 or P<0.01), and immunohistochemical staining showed that NLRP3 was mainly expressed in renal tubular epithelial cells and interstitial macrophages, caspase-1 and IL-1β were mainly found in the cytoplasm of renal tubular epithelial cells. After BHD treatment, the expression levels of each protein were decreased compared with CIH group (P<0.05). Conclusion: Banxia Houpu decoction can reduce the kidney damage by inhibiting the expression of related molecules in the NLRP3/Casapse-1/IL-1β signaling pathway.

Improving effects of eplerenone on atrial remodeling induced by chronic intermittent hypoxia in rats

ObjectiveAtrial fibrillation (AF) is closely associated with the overactivation of the renin-angiotensin-aldosterone system. Large cohort studies and recent meta-analyses have shown that the utilization of mineralocorticoid receptor antagonists has positive effects on the prevention and development of AF. This study aimed to investigate the effects of eplerenone on atrial remodeling in AF model rats and elucidate its intrinsic mechanism. MethodsNinety male Sprague-Dawley rats were randomly divided into the control group, chronic intermittent hypoxia (CIH) group, and CIH-eplerenone intervention (CIH-E) group. Rats in the CIH and CIH-E groups received CIH for 6 weeks, and rats in the CIH-E group were additionally administered eplerenone gavage (10 mg/kg/d). After modeling, the baseline parameters of each group were examined. Histopathology, molecular biology, isolated electrophysiology, and patch clamp experiments were performed after sampling. ResultsCompared with the control group, rats in the CIH group showed atrial enlargement, significant aggravated fibrosis, upregulated JAK/STAT3 pathway, shortened effective refractory period (ERP), increased AF inducibility, and decreased peak current density of characteristic voltage-gated ion channels in atrial myocytes. After eplerenone intervention, rats in the CIH-E group had a smaller atrial diameter than those in the CIH group. Furthermore, downregulated JAK/STAT3 pathway, prolonged ERP, decreased AF inducibility, and increased peak current density of characteristic ion channels were also observed in the CIH-E group. ConclusionsCIH induced significant atrial remodeling in rats and eplerenone significantly ameliorated the atrial remodeling caused by CIH. This could be attributed to the downregulation of the JAK/STAT3 pathway and the increase in the characteristic ion current density of atrial myocytes.

Chronic Hypoxia Blunts the Hypoxic Ventilatory Response in Neonatal and Adult Rats

Chronic hypoxia (CH) may affect the control of breathing differently in neonatal versus adult mammals. It is widely accepted that CH blunts the hypoxic ventilatory response (HVR) in neonatal rats but augments hypoxic ventilation in adult rats. However, there is also evidence that longer durations of CH can progressively attenuate the HVR in adult rats too. Therefore, we predicted that short durations of CH (3 days) would blunt the HVR in neonatal rats and augment the HVR in adult rats, but that longer durations of CH (7 days) would blunt the HVR in adult rats. To test these predictions, rats were exposed to 12% O2 (CH) or room air (Control) for 3 days as neonates (from P0 to P3, or from P7 to P10) or as young adults. Baseline ventilation (21% O2) and the acute HVR (12% O2) were measured by plethysmography immediately following the exposure. The adult rats were then returned to the CH and Control chambers for 4 more days before repeating the breathing measurements. Although Sprague‐Dawley rats were used in all experiments, adults from two different commercial suppliers (Charles River Laboratories and Envigo) were used to determine whether genetic background might influence the results. Baseline ventilation was greater in all CH groups regardless of their age, consistent with ventilatory acclimatization. With the exception of CH rats at P10 in which peak hypoxic ventilation (i.e., minute ventilation during the first minute of 12% O2) was also greater than in Controls, hypoxic ventilation was generally similar between CH and Control groups or reduced in the CH group. Accordingly, the change in ventilation from baseline (i.e., HVR) was blunted by CH regardless of the age of the rats, the duration of the CH exposure (adults only), or the substrain of Sprague‐Dawley rat (adults only). The order in which test gases were presented during breathing measurements (i.e., 21% O2 – 12% O2 vs. 12% O2 – 21% O2) did not influence the calculated HVR in adult rats. We conclude that the respiratory plasticity elicited by normobaric CH is similar across ages in Sprague‐Dawley rats.

Role of raphe magnus 5-HT1A receptor in increased ventilatory responses induced by intermittent hypoxia in rats

BackgroundIntermittent hypoxia induces increased ventilatory responses in a 5-HT-dependent manner. This study aimed to explore that effect of raphe magnus serotonin 1A receptor (5-HT1A) receptor on the increased ventilatory responses induced by intermittent hypoxia.MethodsStereotaxic surgery was performed in adult male rats, and acute and chronic intermittent hypoxia models were established after recovery from surgery. The experimental group received microinjections of 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the raphe magnus nucleus (RMg). Meanwhile, the control group received microinjections of artificial cerebrospinal fluid instead of 8-OH-DPAT. Ventilatory responses were compared among the different groups of oxygen status. 5-HT expressions in the RMg region were assessed by immunohistochemistry after chronic intermittent hypoxia.ResultsCompared with the normoxia group, the acute intermittent hypoxia group exhibited higher ventilatory responses (e.g., shorter inspiratory time and higher tidal volume, frequency of breathing, minute ventilation, and mean inspiratory flow) (P < 0.05). 8-OH-DPAT microinjection partly weakened these changes in the acute intermittent hypoxia group. Further, compared with the acute intermittent hypoxia group, rats in chronic intermittent hypoxia group exhibited higher measures of ventilatory responses after 1 day of intermittent hypoxia (P < 0.05). These effects peaked after 3 days of intermittent hypoxia treatment and then decreased gradually. Moreover, these changes were diminished in the experimental group. 5-HT expression in the RMg region increased after chronic intermittent hypoxia, which was consistent with the changing trend of ventilatory responses. While activation of the 5-HT1A receptor in the RMg region alleviated this phenomenon.ConclusionsThe results indicate that RMg 5-HT1A receptor, via changing the expression level of 5-HT in the RMg region, is involved in the modulation of the increased ventilatory responses induced by intermittent hypoxia.

Platelets and High-Altitude Exposure: A Meta-Analysis.

Wang, Yuliang, Xuewen Huang, Weibo Yang, and Qingxian Zeng. Platelets and high-altitude exposure: a meta-analysis. High Alt Med Biol. 23:43-56, 2022. Background: How high-altitude hypoxia influences platelets is controversial. We attempted to quantify the impact of high-altitude exposure on platelets through meta-analysis. Methods: We systematically searched electronic databases (PubMed, Embase, Web of Science, VIP, Wanfang, and CNKI) and identified articles reporting an association between platelet count (PC) or platelet indices (platelet distribution width, mean platelet volume [MPV], and plateletcrit) and high-altitude exposure. The mean and standard deviation were extracted, and the standard mean difference (SMD) was estimated using random-effects models. Stata 15.3 was used to analyze statistical data. Results: Thirty-two studies were ultimately included. For acute high-altitude hypoxia (1-14 days), no significant difference was detected, even in patients with acute mountain disease. For the chronic high-altitude hypoxia (≥1 month) group, a significant decrease in PC (SMD [95% confidence interval, CI] = -0.34 [-0.63 to -0.04]) and increase in MPV (SMD [95% CI] = 1.55 [0.60 to 2.49]) were detected compared with those in the control group. Subgroup analysis showed that the tendency was more obvious in the group with longer exposure (≥1 year). Moreover, the PC of the chronic mountain sickness group was less compared with the healthy altitude control group (SMD [95% CI] = -1.82 [-2.74 to -0.91]). Conclusion: A reduced PC and an increased MPV are associated with chronic exposure to high-altitude hypoxia. Moreover, acute high-altitude exposure has no significant influence on platelets.

Establishment of a lncRNA-miRNA-mRNA network in a rat model of atrial fibrosis by whole transcriptome sequencing.

Dysregulation of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) plays important roles in atrial fibrillation (AF). This study aimed to identify crucial lncRNAs, miRNAs, and mRNAs in AF based on whole transcriptome sequencing. Thirty Sprague Dawley rats were randomly stratified into control and chronic intermittent hypoxia (CIH) groups (n = 15 in each). Hematoxylin-eosin staining, Masson staining, immunohistochemical assay, and western blotting were used to evaluate this model. Thereafter, atrial tissues were sent for whole transcriptome sequencing. Finally, fibrosis-related competing endogenous RNA (ceRNA) regulatory networks were built, and the relative levels of lncRNAs, miRNAs, and mRNAs were validated by real-time quantitative polymerase chain reaction (RT-qPCR) or western blotting. A CIH-induced atrial fibrosis rat model was successfully constructed. After sequencing, 268 differentially expressed lncRNAs (DELs), 20 differentially expressed miRNAs (DEMs), and 436 differentially expressed genes (DEGs) were identified. Functional analyses showed that these DEGs were associated with several processes and pathways, including "cell division," "IL-17 signaling pathway," "NOD-like receptor signaling pathway," and "cell adhesion molecules." Fibrosis-related ceRNA networks were then built, comprising five lncRNAs, seven miRNAs, and 19 DEGs. RT-qPCR and western blotting results showed that the patterns of lncRNAs (NONRATT016396.2, NONRATT001596.2, NONRATT011456.2), miRNAs (miR-10b-3p, miR-29b-3p), and mRNAs (Gng7 and Wnt2b) were consistent with sequencing analyses. The DELs, DEMs, and DEGs identified in this study may participate in atrial fibrosis processes, and the occurrence and progression of AF.

Prenatal Chronic Hypoxia in Rats Leads to Insulin Resistance and Hypertension in Adult Offspring

Abstract Background To investigate the effects of chronic intrauterine hypoxia on insulin resistance, hypertension, and the correlation between them in adult offspring rats. Methods A total of 25 pregnant Sprague Dawley rats were randomly assigned into 4 prenatal chronic hypoxia (H) groups (10% ± 1% oxygen) and a control group (21% oxygen). The H groups were divided into whole (1–21 day), early (1–7 day), mid (8–14 day), and late (15–21 day) gestational hypoxia groups (H1, H2, H3, and H4, respectively) with pregnant rats being housed in a hypoxia box for 3 hours per day. Five male and 5 female offspring in each group were studied at 1 day, 3 months, and 6 months old. Blood pressure, fasting blood glucose, fasting serum insulin, and insulin resistance index were determined. Results The mean blood pressure of offspring rats in H groups was higher at 3 months, and further increased at 6 months old compared to the control group (P &amp;lt; 0.05). The fasting blood glucose and homeostasis model insulin resistance index (HOMA-IR) of male and female offspring in the whole pregnancy (H1) and early pregnancy (H2) hypoxia groups were significantly higher than those in the control group at 6 months (P &amp;lt; 0.05). Fasting blood glucose and HOMA-IR were positively correlated with mean blood pressure (P &amp;lt; 0.05). The renal mass index in H2 group was lower at 3 months, and further decreased at 6 months compared to controls (P &amp;lt; 0.05). The mRNA and protein levels of insulin receptor, insulin receptor substrate (IRS-1 and IRS-2) in the kidneys in hypoxia groups were significantly decreased at 6 months in H1 and H2 hypoxia groups when compared with controls (P &amp;lt; 0.05). Conclusions Chronic intrauterine hypoxia causes insulin resistance and hypertension in adult offspring rats through poor intrauterine growth environment, and insulin resistance is positively associated with hypertension.

Angiotensin II receptor blocker irbesartan attenuates sleep apnea-induced cardiac apoptosis and enhances cardiac survival and Sirtuin 1 upregulation.

The purpose of this study was to investigate whether or not angiotensin II type 1 receptor blocker irbesartan (ARB) with a partial agonist of PPAR-γ could protect against chronic nocturnal intermittent hypoxia (CIH)-induced cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis. Sprague-Dawley rats were in a normoxic control group (CON-G), or rats werein a chronic nocturnal intermittent hypoxia group (HP-G, from 3 to 7% oxygen versus 21% oxygen per forty seconds cycle, nocturnally 8h per day for 1month), or rats were in a chronic nocturnal intermittent hypoxia group pretreated withARB (50mg/kg/day, S.C.) (ARB-HP-G). Echocardiography, H&E staining, TUNEL staining, and Western blotting were measured inthe left ventricle. Hypoxia-induced SIRT1 degradation, Fas receptors, FADD, active caspase-8 and caspase-3 (Fas/FasL apoptotic pathway) and Bax, tBid, active caspase-9 and -3 (mitochondrial apoptotic pathway) and TUNEL-positive apoptosis were reduced in ARB-HP-G when compared with HP-G. IGF-I, IGF1 receptor, p-PI3k, p-Akt, Bcl2, and Bcl-XL (IGF1/PI3K/AKT pro-survival pathway) were increased in ARB-HP-G compared to HP-G. Our findings suggest that the ARB may prevent cardiac Fas/FasL to mitochondrial apoptotic pathways and enhance cardiac IGF1/PI3K/AKT pro-survival pathway in the sleep apnea model associated with JNK de-activation and SIRT1 upregulation. ARB prevents chronic sleep apnea-enhanced cardiac apoptosis via enhancing survival pathways.

Transcriptional landscape in rat intestines under hypobaric hypoxia.

Oxygen metabolism is closely related to the intestinal homeostasis environment, and the occurrence of many intestinal diseases is as a result of the destruction of oxygen gradients. The hypobaric hypoxic environment of the plateau can cause dysfunction of the intestine for humans, such as inflammation. The compensatory response of the small intestine cells to the harsh environment definitely changes their gene expression. How the small intestine cells response the hypobaric hypoxic environment is still unclear. We studied the rat small intestine under hypobaric hypoxic conditions to explore the transcriptional changes in rats under acute/chronic hypobaric hypoxic conditions. We randomly divided rats into three groups: normal control group (S), acute hypobaric hypoxia group, exposing to hypobaric hypoxic condition for 2 weeks (W2S) and chronic hypobaric hypoxia group, exposing to hypobaric hypoxic condition for 4 weeks (W4S). The RNA sequencing was performed on the small intestine tissues of the three groups of rats. The results of principal component analysis showed that the W4S and W2S groups were quite different from the control group. We identified a total of 636 differentially expressed genes, such as ATP binding cassette, Ace2 and Fabp. KEGG pathway analysis identified several metabolic and digestive pathways, such as PPAR signaling pathway, glycerolipid metabolism, fat metabolism, mineral absorption and vitamin metabolism. Cogena analysis found that up-regulation of digestive and metabolic functions began from the second week of high altitude exposure. Our study highlights the critical role of metabolic and digestive pathways of the intestine in response to the hypobaric hypoxic environment, provides new aspects for the molecular effects of hypobaric hypoxic environment on intestine, and raises further questions about between the lipid metabolism disorders and inflammation.

Endogenous Endothelin‐1 Contributes to Enhanced Basal Pulmonary Arterial Tone Following Chronic Hypoxia: Role of Mitochondria‐Derived Reactive Oxygen Species

Previous studies from our laboratory demonstrate the importance of mitochondria-derived reactive oxygen species (mitoROS) in the development of pulmonary hypertension after chronic hypoxia (CH) exposure. Furthermore, we have identified a major role for the endothelium to augment mitoROS-dependent pulmonary vascular tone following CH. However, the mechanism of this response remains unclear. We hypothesized that the endogenous vasoconstrictor peptide, endothelin-1 (ET-1), facilitates mitoROS-dependent increases in basal tone after CH exposure. To test our hypothesis, we measured basal tone by videomicroscopy in isolated, pressurized, small pulmonary arteries [~150 μm inner diameter (i.d.)] from normoxic and CH (4 wk, 0.5 atm) rats with and without the ETA receptor and ETB receptor inhibitors, BQ123 and BQ788 (10 μM each), respectively. Parallel protocols were conducted in the presence of the mitochondria-targeted antioxidant, MitoQ (1 μM). All experiments were performed in the presence of the nitric oxide (NO) synthase inhibitor, Nω-nitro-L-arginine (300 μM), to limit the influence of endogenous NO. Pulmonary arterial tone was calculated as the percent difference in i.d. between Ca2+-free and Ca2+-containing conditions. To evaluate the contribution of mitoROS to ET-1-mediated vasoconstriction, we further assessed vasoconstrictor responses (percentage of baseline i.d.) to serial concentrations of exogenous ET-1 (10-11 to 10-7 M) in the presence or absence of MitoQ in endothelium-disrupted pulmonary arteries from each group. Additional experiments employed confocal microscopy to measure ET-1 (1 nM)-induced mitoROS production in primary cultures of pulmonary arterial smooth muscle cells (PASMCs) from control and CH rats using the fluorescent mitochondrial superoxide indicator MitoSOX (10 μM). Antimycin A (10 µM) treatment, which stimulates mitoROS production from complex III of electron transport chain, was used as a positive control. Both MitoQ and the combined administration of ETA and ETB receptor blockers abolished the effect of CH to increase basal tone (P<0.05). Arteries from CH rats also exhibited greater constriction to exogenous ET-1 (at 1 nM) compared to vessels from normoxic controls, which was prevented by MitoQ (P<0.05). Consistent with these findings, application of ET-1 significantly increased mitoROS production in PASMCs from CH rats (P<0.05), but not control animals. Application of antimycin A led to mitoROS generation in both control and CH groups (P<0.05). We conclude that endogenous ET-1 promotes pulmonary arterial constriction through mitoROS signaling in PASMCs following CH. These findings advance our understanding of the mechanistic basis for the vasoconstrictor component of CH-induced pulmonary hypertension.

CB1 receptor antagonist rimonabant protects against chronic intermittent hypoxia-induced renal injury in rats

BackgroundObstructive sleep apnoea (OSA) induced chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH). Our study investigate the mechanism underlying CIH-induced renal damage and whether the cannabinoid receptor 1 (CB1R) antagonist rimonabant (Ri) alleviates CIH-induced renal injury.MethodsMale Sprague-Dawley rats were randomly divided into five groups: one normal control (NC) group, two chronic intermittent hypoxia (CIH) groups, and two CIH + Ri groups. Rats in the NC groups were exposed to room air, while the CIH groups were exposed to a CIH environment for 4 weeks (4w CIH group) and 6 weeks (6w CIH group), respectively. Additionally, rats in the CIH + Ri groups were administered 1.5 mg/kg/day Ri for 4 weeks (4w CIH + Ri group) and 6 weeks (6w CIH + Ri group), respectively. Following this, the rats were euthanized and kidneys were excised for downstream analysis. In the renal tissues, the morphological alterations were examined via haematoxylin eosin (HE) staining and periodic acid schiff (PAS) staining, CB1R, Fis1, Mfn1, and p66Shc expression was assessed through western blot and immunohistochemistry, and the mitochondrial ultrastructural changes in kidney sections were assessed by electron microscopy.ResultsCB1R expression in the 4w and 6w CIH groups was significantly elevated, and further increased with prolonged hypoxia; however, Ri prevented the increase in CIH-induced CB1R expression. Fis1 and p66Shc expression in the CIH groups were increased, but Mfn1 expression decreased. Ri decreased Fis1 and p66Shc expression and increased Mfn1 expression. Renal damage in the 4w or 6w CIH + Ri group was evidently improved compared with that in the 4w or 6w CIH group. CB1R expression was positively correlated with Fis1 and p66Shc and negatively correlated with Mfn1. Meanwhile, electron microscopy showed that the percentage of fragmented mitochondria in the tubular cells in each group was consistent with the trend of CB1R expression.ConclusionCIH causes endocannabinoid disorders and induces abnormal mitochondrial dynamics, resulting in renal injury. Treatment with CB1R antagonists reduces CIH-induced renal damage by inhibiting dysregulated renal mitochondrial dynamics.

Medical Image Analysis of Telmisartan-Induced Protection in Hippocampal CA1 After Chronic Intermittent Hypoxia

Objective: In this paper, we evaluate medical image analysis in hippocampus, immunohistochemistry analyzed and oxidative stress-mediated injury induced by chronic intermittent hypoxia on the mouse hippocampal CA1 area and the protective effects of telmisartan (TEL) on oxidative stress-mediated injury. Methodology: C57B6J mice have been randomly categorized as chronic intermittent hypoxia (CIH) group, CIH + telmisartan (CIH + TEL) group, the room air control group and blank control group, and examined during a period of 12 weeks. Brain images were obtained by Computed tomography scan, spatial learning and memory abilities were tested, and p47 NADPH oxidase subunit (p47PHOX) and 8-hydroxy-guanosine (8-OHG) were measured in the hippocampal CA1 area by immunohistochemistry and analyzed by Image-Pro Plus 6.0. Results: (1) After 12 weeks, there were no abnormalities in mice brain by CT scan. (2) Spatial learning ability measured by escape latency from the Morris water maze in the hypoxia group decreased, while intervention with telmisartan improved the hypoxiainduced spatial learning deficit (F = 3.04, P = 0.045). There exist no differences in spatial memory among any groups. (3) p47PHOX immunostaining significantly increased in hippocampal CA1 area after CIH, which was reduced by TEL intervention. (4) CIH significantly increased 8-OHG immunostaining in the hippocampal CA1 area, while intervention with TEL significantly reduced 8-OHG immunostaining. Conclusions: Telmisartan significantly reduced expression of NADPH oxidase p47PHOX and 8-OHG in CIH mice, and improved hippocampusdependent learning, suggesting that telmisartan can reduce CIH-induced neuronal oxidative stress-mediated injury.

Клінічний випадок легеневої гіпертензії, асоційованої з рідкісною хворобою легень

У статті проаналізовано клінічний випадок легеневої гіпертензії (ЛГ), асоційованої з рідкісним захворюванням легень – лімфангіолейоміоматозом. Висвітлюються питання: критерії діагностики цього захворювання, поширеність, основні шляхи патогенезу, зокрема механізми розвитку ЛГ, клінічні вияви, методи лікування. Зроблено висновки щодо особливостей цього випадку, а саме: це рідкісне захворювання легень, яке можливо діагностувати лише за наявності досвіду; захворювання діагностовано у відносно пізньому віці, що є нетиповим (як правило, більшість жінок з таким діагнозом – дітородного віку); за помірних змін функції легень спостерігалася значна ЛГ, яка потребувала додаткового обстеження в спеціалізованому центрі; незважаючи на діагностоване ураження легень та загальні рекомендації не призначати специфічну терапію при цій формі ЛГ, як виняток, простагландини були застосовані, що поліпшувало клінічний стан пацієнтки. Спираючись на останні рекомендації 6-го Всесвітнього симпозіуму із легеневої гіпертензії (Ніцца, 2018), розглядаються особливості діагностики та лікування ЛГ, пов’язані з гіпоксією і хворобами легень (група 3), та їх відмінності від легеневої артеріальної гіпертензії (група 1). Особливий наголос робиться на необхідності індивідуального підходу до призначення специфічної терапії ЛГ пацієнтам із захворюванням легень і підвищенням тиску в легеневій артерії та проведення клінічних досліджень із вивчення її впливу на перебіг захворювання.

Lower Body Weight in Rats Under Hypobaric Hypoxia Exposure Would Lead to Reduced Right Ventricular Hypertrophy and Increased AMPK Activation.

BackgroundBoth 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.MethodsSixty 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.ResultsA 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).ConclusionMaintaining 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.