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The endoplasmic reticulum (ER) is important to cells because of its essential functions, including synthesizing three major nutrients and ion transport. When cellular homeostasis is disrupted, ER quality control (ERQC) system is activated effectively to remove misfolded and unfolded proteins through ER-phagy, ER-related degradation (ERAD), and molecular chaperones. When unfolded protein response (UPR) and ER stress are activated, the cell may be suffering a huge blow, and the most probable consequence is apoptosis. The membrane contact points between the ER and sub-organelles contribute to communication between the organelles. The decrease in oxygen concentration affects the morphology and structure of the ER, thereby affecting its function and further disrupting the stable state of cells, leading to the occurrence of disease. In this study, we describe the functions of ER-, ERQC-, and ER-related membrane contact points and their changes under hypoxia, which will help us further understand ER and treat ER-related diseases. [Display omitted] • The structure and function of the ER stable state is very important for cells. Hypoxia affects the ER. • ERQCs are important for maintaining ER function. ERQCs include Ubiquitin-proteasome system, ER phagocytosis, ER-related degradation (ERAD), Molecular chaperone, Unfolded protein response (UPR), ER stress. Hypoxia affects ERQC. • ER-related MCS have ER and mitochondrial contact points (MERC), ER and Golgi contact points (ERGIC), and ER and lipid droplets (ER-LD). Hypoxia affects MCS. [ABSTRACT FROM AUTHOR]

The gut microbiota plays a crucial role in maintaining host nutrition, metabolism, and immune homeostasis, particularly in extreme environmental conditions. However, the regulatory mechanisms of the gut microbiota in animal organisms hypobaric hypoxia exposure require further study. We conducted a research by comparing SD rats treated with an antibiotic (ABX) cocktail and untreated SD rats that were housed in a low-pressure oxygen chamber (simulating low pressure and hypoxic environment at 6000 m altitude) for 30 days. After the experiment, blood, feces, and lung tissues from SD rats were collected for analysis of blood, 16S rRNA amplicon sequencing, and non-targeted metabolomics. The results demonstrated that the antibiotic cocktail-treated SD rats exhibited elevated counts of neutrophil (Neu) and monocyte (Mon) cells, an enrichment of sulfate-reducing bacteria (SBC), reduced levels of glutathione, and accumulated phospholipid compounds. Notably, the accumulation of phospholipid compounds, particularly lysophosphatidic acid (LPA), lipopolysaccharide (LPS), and lysophosphatidylcholine (LPC), along with the aforementioned changes, contributed to heightened oxidative stress and inflammation in the organism. In addition, we explored the resistance mechanisms of SD rats in low-oxygen and low-pressure environments and found that increasing the quantity of the Prevotellaceae and related beneficial bacteria (especially Lactobacillus) could reduce oxidative stress and inflammation. These findings offer valuable insights into enhancing the adaptability of low-altitude animals under hypobaric hypoxia exposure. To investigate the impacts of in hypobaric hypoxia exposure on animal physiological functions and potential biological regulatory mechanisms, we conducted a research by comparing SD rats treated with an antibiotic (ABX) cocktail and untreated SD rats that were housed in a low-pressure oxygen chamber (simulating low pressure and hypoxic environment at 6000 m altitude) for 30 days. In our study, we discovered that the antibiotic intervention worsened oxidative stress and inflammatory responses in SD rats under hypobaric hypoxia exposure. We further investigated the resistance mechanisms of SD rats in low-oxygen and low-pressure environments and identified that increasing the abundance of Prevotellaceae and other beneficial bacteria, particularly Lactobacillus, could alleviate oxidative stress and inflammation. These findings offer valuable insights into enhancing the adaptability of low-altitude animals under hypobaric hypoxia exposure. [Display omitted] • The gut microbiota plays a crucial role in maintaining host nutrition, metabolism, and immune homeostasis, particularly in extreme environmental conditions. However, the regulatory mechanisms of the gut microbiota in animal organisms hypobaric hypoxia exposure require further study. In this study, we employed a combined strategy of 16S and metabolomics analyses. We aimed to investigate the impacts of Antibiotic (ABx) cocktail on oxidative stress and inflammatory response in Sprague-Dawley (SD) rats exposed to hypobaric hypoxia exposure, exploring the resistance mechanisms of SD rats in low-oxygen and low-pressure environments. In summary, we have found that under hypobaric hypoxia exposure, antibiotic intervention exacerbates oxidative stress and body inflammation in SD rats. On the other hand, SD rats can mitigate oxidative stress and inflammation by increasing the abundance of beneficial bacteria such as Prevotellaceae and Lactobacillus in their bodies. These findings offer insights into enhancing the adaptability of low-altitude animals to high-altitude environments. [ABSTRACT FROM AUTHOR]

• The role of inflammation in pulmonary hypertension is gradually important. • Dynamic observation of Macrophage-Derived inflammation in mice with hypoxia-induced pulmonary hypertension. • Hypoxic Pulmonary Hypertension inflammation can be through activation of IL-33 Signaling Pathway. • Pulmonary artery remodeling in HPH mice worsens progressively in a time-dependent manner, with inflammatory predominating in the early stage and pulmonary vascular remodeling occurring in the later stage. The role of inflammation in pulmonary hypertension is gradually gaining increasing research attention. However, no previous study has evaluated the characteristics of inflammation during chronic hypoxia-induced pulmonary hypertension. Therefore, the aim of this study was to investigate the characteristics of the inflammatory process involved in hypoxia-induced pulmonary hypertension in mice. The current study evaluated from day 4 to day 28 of hypoxia, the PAAT and PAAT/PET decreased, accompanied by pulmonary vascular remodeling and right ventricular hypertrophy, as well as increased numbers of CD68 macrophages. The expression of the pro-inflammatory factors IL-1β and IL-33 increased, but decreased on day 28. The expression of IL-12 increased from day 4 to day 28, whereas that of the anti-inflammatory factor IL-10 in lung tissue decreased. Furthermore, the expression of the IL-33/ST2 signaling pathway also increased over time under hypoxic conditions. In conclusion, pulmonary artery remodeling in HPH mice worsens progressively in a time-dependent manner, with inflammatory cell infiltration predominating in the early stage and pulmonary vascular remodeling occurring in the later stage. IL-33/ST2 signaling pathways in hypoxia-induced PAH mice. [Display omitted] [ABSTRACT FROM AUTHOR]

Chronic hypoxia (CH) is characterized by long-term hypoxia that is associated with microvessel proliferation and basal membrane (BM) degradation in tissues. The IL-6/JAK2/STAT3/MMP-9 pathway has been described in a variety of human cancers and plays an essential role in microvessel proliferation and BM degradation. Therefore, this study investigated the role of the IL-6/JAK2/STAT3/MMP-9 pathway in hypoxia-mediated microvessel proliferation and BM degradation in the rat bone marrow. Eighty pathogen-free Sprague Dawley male rats were randomly divided into four groups (20 per group)—control group, CH group (exposed to hypoxia in a hypobaric chamber at a simulated altitude of 5000 m for 28 d), CH + STAT3 inhibitor group (7.5 mg/kg/d), and CH + DMSO group. Microvessel density (MVD) and BM degradation in the bone marrow were determined by immunofluorescence staining and transmission electron microscopy. Serum IL-6 levels were assessed by enzyme-linked immunosorbent assay (ELISA), and the levels of P-JAK2, P-STAT3, and MMP-9 were assessed by western blot analysis and real-time reverse transcription PCR (RT-PCR). Hypoxia increased serum IL-6 levels, which in turn increased JAK2 and STAT3 phosphorylation, which subsequently upregulated MMP-9. Overexpression of MMP-9 significantly promoted the elevation of MVD and BM degradation. Inhibition of STAT3 using an inhibitor, SH-4-54, significantly downregulated MMP-9 expression and decreased MVD and BM degradation. Surprisingly, STAT3 inhibition also decreased serum IL-6 levels and JAK2 phosphorylation. Our results suggest that the IL-6/JAK2/STAT3/MMP-9 pathway might be related to CH-induced microvessel proliferation and BM degradation in the bone marrow. [ABSTRACT FROM AUTHOR]

Exposure to hypoxia, through ascension to high altitudes (HAs), air travel, or human disease, is associated with an increased incidence of thrombosis in some settings. Mechanisms underpinning this increased thrombosis risk remain incompletely understood, and the effects of more sustained hypoxia on the human platelet molecular signature and associated functional responses have never been examined. We examined the effects of prolonged (≥2 months continuously) hypobaric hypoxia on platelets isolated from subjects residing at HA (3,700 meters) and, for comparison, matched subjects residing under normoxia conditions at sea level (50 meters). Using complementary transcriptomic, proteomic, and functional methods, we identified that the human platelet transcriptome is markedly altered under prolonged exposure to hypobaric hypoxia at HA. Among the significantly, differentially expressed genes (mRNA and protein), were those having canonical roles in platelet activation and thrombosis, including membrane glycoproteins (e.g. GP4, GP6, GP9), integrin subunits (e.g. ITGA2B), and alpha-granule chemokines (e.g. SELP, PF4V1). Platelets from subjects residing at HA were hyperactive, as demonstrated by increased engagement and adhesion to fibrinogen, fewer alpha granules by transmission electron microscopy, increased circulating PF4 and ADP, and significantly enhanced clot retraction. In conclusion, we identify that prolonged hypobaric hypoxia exposure due to HA alters the platelet transcriptome and proteome, triggering increased functional activation responses that may contribute to thrombosis. Our findings may also have relevance across a range of human diseases where chronic hypoxia, platelet activation, and thrombosis are increased. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Srolo Bzhtang (SBT), a traditional Tibetan medicine formula, was composed of three herbs, Solms-Laubachia eurycarpa , Bergenia purpurascens , Glycyrrhiza uralensis , and one lac, and was first documented in the ancient Tibetan medical work Four Medical Tantras (rGyud-bzhi) in the eighth century AD. It has been widely used to treat lung "phlegm-heat" syndromes such as chronic bronchitis and chronic obstructive pulmonary disease (COPD). Objective The aim of this study was to evaluate the potential influences of aqueous extract of SBT on airway inflammation and mucus secretion and to reveal the underlying mechanism in a rat model of cigarette smoke (CS)-induced chronic bronchitis (CB). Materials and methods Sixty male Sprague-Dawley rats were randomly divided to six groups: control (room air exposure), model (CS exposure), DEX (CS exposure and 0.2 mg/kg/day dexamethasone), and three SBT (CS exposure and 1.67, 2.50, and 3.34 g/kg/day SBT) groups. DEX and the three doses of SBT were administered by oral gavage every day for eight weeks. Pathological changes and mucus expression in the lung tissue were determined by hematoxylin and eosin (H&E), Alcian blue-periodic acid-Schiff (AB-PAS) and immunohistochemical staining. The levels of cytokines in bronchoalveolar lavage fluid (BALF) were assessed by ELISA. Western blot analysis and qRT-PCR were performed to explore the effects of SBT on the expression of IL-13, STAT6 and MUC5AC. Results Pretreatment with SBT attenuated the TNF-α, IL-8, IL-13 expression levels in BALF and the inflammatory cell infiltration in bronchial walls and peribronchial lung tissue. SBT exhibited a dose-dependent downregulation of MUC5AC expression as assessed by AB-PAS and immunohistochemical staining. The protein and mRNA levels of IL-13, STAT6/p-STAT6 and MUC5AC were also downregulated by SBT preconditioning. Conclusion These results for the first time demonstrated that SBT exhibited protective effects on CS-induced airway inflammation and MUC5AC hypersecretion, which might be related to the downregulation of the IL-13/STAT6 signaling pathway. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Hypoxia-induced pulmonary hypertension (HPH) is a severe condition associated with significant morbidity and mortality in people living at high altitude. Tsantan Sumtang, a traditional Tibetan medicine, has been routinely used for the treatment of cardiopyretic disease, as well as stenocardia. Interestingly, our previous research found that Tsantan Sumtang improved HPH in rats maintaining in a hypobaric chamber. We performed a series of experiments to test the indexes of vasoconstriction and vascular remodeling, the key pathophysiological characteristics of HPH. Our results showed that Tsantan Sumtang relaxed noradrenaline (NE)-precontracted rat pulmonary artery rings in a concentration-dependent manner in vitro. The PGI2-cAMP (prostaglandin I2-cyclic adenosine monophosphate) pathway, NO-cGMP (nitric oxide-cyclic guanosine monophosphate) pathway, and the opening of K+ channels (inward rectifier K+ channels, large conductance Ca2+-activated K+ channels, and voltage-dependent K+ channels) might play major roles in the vasorelaxation effect. In vivo, the administration of Tsantan Sumtang resulted in a substantial decrease in the rat mean pulmonary artery pressure (mPAP) and the right ventricular hypertrophy index (RVHI). The reduction of thickness of small pulmonary arterial wall and the WT% (the ratio of the vascular wall thickness to the vascular diameter) were observed. The smooth muscle muscularization of the arterials was alleviated by Tsantan Sumtang treatment at the same time. Tsantan Sumtang also reduced remodeling of pulmonary arterioles by suppressing the expression of proliferating cell nuclear antigen (PCNA), α-smooth muscle actin (α-SMA), cyclin D1, and cyclin-dependent kinase 4 (CDK4) through inhibition of p27Kip1 degradation. Therefore, Tsantan Sumtang could be applied as a preventative medication for HPH, which would be a new use for this traditional medicine. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Rhodiola algida var. tangutica (Maxim.) S.H. Fu is a perennial plant of the Crassulaceae family that grows in the mountainous regions of Asia. The rhizome and roots of this plant have been long used as Tibetan folk medicine for preventing high latitude sickness. Aim of the study The aim of this study was to determine the effect of bioactive fraction from R. algida (ACRT) on chronic hypoxia-induced pulmonary arterial hypertension (HPAH) and to understand the possible mechanism of its pharmacodynamic actions. Materials and methods Male Sprague-Dawley rats were separated into five groups: control group, hypoxia group, and hypoxia+ACRT groups (62.5, 125, and 250 mg/kg/day of ACRT). The chronic hypoxic environment was created in a hypobaric chamber by adjusting the inner pressure and oxygen content for 4 weeks. After 4 weeks, major physiological parameters of pulmonary arterial hypertension such as mPAP, right ventricle index (RV/LV+S, RVHI), hematocrit (Hct) levels and the medial vessel thickness (wt%) were measured. Protein and mRNA expression levels of proliferating cell nuclear antigen (PCNA), cyclin D1, p27Kip1 and cyclin-dependent kinase 4 (CDK4)) were detected by western blotting and real time PCR respectively. Chemical profile of ACRT was revealed by ultra performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UHPLC-Q-TOF-MS/MS). Results The results showed that a successful HPAH rat model was established in a hypobaric chamber for 4 weeks, as indicated by the significant increase in mPAP, RV/LV+S, RV/BW and wt%. Compared with the normal group, administration of ACRT reduced mPAP, right ventricular hypertrophy, pulmonary small artery wall thickness, and damage in ultrastructure induced by hypoxia in rats. PCNA, cyclin D1, and CDK4 expression was reduced ( p <0.05), and p27Kip1 expression increased ( p <0.05) in hypoxia+ACRT groups compared to hypoxia. 38 constituents in bioactive fraction were identified by UHPLC-Q-TOF-MS/MS. Conclusion Our results suggest that ACRT could alleviate chronic hypoxia-induced pulmonary arterial hypertension. And its anti-proliferation mechanism in rats based on decreasing PCNA, cyclin D1, CDK4 expression level and inhibiting p27Kip1 degradation. [ABSTRACT FROM AUTHOR]

Tibetans have lived at high altitude for generations and are thought to be genetically adapted to hypoxic environments. Most are protected from hypoxia-induced polycythemia, and a haplotype of EPAS1, encoding hypoxia-inducible factor (HIF-2α), has been associated with lower hemoglobin levels. We earlier reported a Tibetan-specific EGLN1 haplotype encoding PHD2 which abrogates HIF augmentation in hypoxia. We genotyped 347 Tibetan individuals from varying altitudes for both the Tibetan-specific EGLN1 haplotype and 10 candidate SNPs in the EPAS1 haplotype and correlated their association with hemoglobin levels. The effect of the EGLN1 haplotype on hemoglobin exhibited age dependency at low altitude, while at higher altitudes, it showed a trend to lower hemoglobin levels in the presence of the Tibetan-selected EPAS1 rs142764723 C/C allele. The observed gene-environment and gene-gene interactions and the moderate effect of the EGLN1 and EPAS1 haplotypes on hemoglobin indicate that other modifiers exist. It remains to be determined whether a blunting of erythropoiesis or other physiological consequences of HIF downregulation are the primary drivers of these genetic adaptations among Tibetans. Key message: [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Tsantan Sumtang is a traditional Tibetan medicine, which has been traditionally used as medicine for the treatment of cardiopyretic disease which is similar to angina. However, the precise and comprehensive mechanism of it pretreatment remain elusive, so in this study, we used proteomics to systematically analyse the therapeutic mechanism of it. Materal and methods Rats were divided into three groups ( n =6): Tsantan Sumtang group (2 g/kg), the model group, the control group (distilled water, 10 ml/kg). Drugs were treated once a day for 20 days. After the last administration of drug, left anterior descending coronary artery ligation in vivo was performed. 5 days latter, the hearts were harvested and we applied HPLC- MS/MS using an isobaric TMTs proteomics technology to analyse the differentially expressed proteins among groups. Results We comfirmed from the data that 752 proteins were differentially expressed in model group when compared with the control group, 314 proteins showed the recovery of the values by Tsantan Sumtang treatment. The differential proteins were analysed by gene ontology, cellular pathways and clustering analyses, most of them were metabolic enzymes. These included glycolytic enzymes, enzymes implicated in fatty acids oxidation and the tricarboxylic acid cycle, various subunits of different mitochondrial electron transfer chain complexes, as well as enzymes involved in antioxidation system. Conclusion Tsantan Sumtang can target and regulate multiple metabolic perturbed pathways, especially it can partially inhibite fatty acid β-oxidation, stimulate glucose metabolism, oxidative phosphorylation and ATP utilization to protect the injured heart. This helped us to understand the molecular therapeutic mechanisms of Tsantan Sumtang on mycardial ischemia. [ABSTRACT FROM AUTHOR]

Objective: The incidence of gastric cancer is high in Chinese Tibetan. This study aimed to identify the differentially expressed microRNAs (miRNAs) and further explore their potential roles in Tibetan with gastric cancer so as to predict potential therapeutic targets. Methods: A total of 10 Tibetan patients (male:female = 6:4) with gastric cancer were enrolled for isolation of matched gastric cancer and adjacent non-cancerous tissue samples. Affymetrix GeneChip microRNA 3.0 Array was employed for detection of miRNA expression in samples. Differential expression analysis between two sample groups was analyzed using Limma package. Then, MultiMiR package was used to predict targets for miRNAs. Following, the target genes were put into DAVID (Database for Annotation, Visualization and Integrated Discovery) to identify the significant pathways of miRNAs. Results: Using Limma package in R, a total of 27 differentially expressed miRNAs were screened out in gastric cancer, including 25 down-regulated (e.g. hsa-miR-148a-3p, hsa-miR-148b-3p and hsa-miR-363-3p) and 2 up-regulated miRNAs. According to multiMiR package, a number of 1445 target genes (e.g. Wnt1, KLF4 and S1PR1) of 13 differentially expressed miRNAs were screened out. Among those miRNAs, hsa-miR-148a-3p, hsa-miR-148b-3p and hsa-miR-363-3p were identified with the most target genes. Furthermore, three miRNAs were significantly enriched in numerous common cancer-related pathways, including "Wnt signaling pathway", "MAPK signaling pathway" and "Jak-STAT signaling pathway". Conclusions: The present study identified a downregulation and enrichment in cancer-related pathways of hsa-miR- 148a-3p, hsa-miR-148b-3p and hsa-miR-363-3p in Tibetan with gastric cancer, which can be suggested as therapeutic targets. [ABSTRACT FROM AUTHOR]

Tibetan Mastiff has adapted to the extreme environment of the Qinghai-Tibetan Plateau. Yet, the underlying mechanisms of its high-altitude-adaptation and origin remains elusive. Here, we generated the draft genomes of Mongolia Mastiff, Tibetan Mastiff, and Canis Lupus. The phylogenetic tree uncovered that Tibetan Mastiff and Mongolia Mastiff were derived from Canis Lupus species. The comparative genomic analyses identified that the expansion of gene families related to DNA repair and damage response, and contraction related to ATPase activity revealed the genetic adaptations of Tibetan Mastiff and Canis Lupus to high altitude. In addition, the Tibetan Mastiff and Canis Lupus had signals of positive selection for genes involved in fatty-acid α/β- oxidation for highland adaptation. Notably, the positively selected TERT of Tibetan Mastiff should be an adaptive trait for correcting DNA damage. These findings suggested that the Tibetan Mastiff and Canis Lupus evolves basic strategies for adaptation to high altitude. • De novo assembled the genome sequence of Mongolia mastiff, Tibetan mastiff, and Canis Lupus with excellent continuity at the contig and scaffold levels. • Tibetan Mastiff and Mongolia Mastiff were derived from Canis Lupus. • The expansion of gene families related to DNA repair and damage response, as well as the contraction related to ATPase activity revealed the genetic adaptations of Tibetan Mastiff and Canis Lupus to high altitude. • The Tibetan Mastiff and Canis Lupus had signals of positive selection for genes involved in fatty-acid α/β-oxidation for highland adaptation. Notably, the positively selected TERT of Tibetan Mastiff should be an adaptive trait for correcting DNA damage. [ABSTRACT FROM AUTHOR]

Tsantan Sumtang, which consists of Choerospondias axillaris (Roxb.) Burtt et Hill, Myristica fragrans Houtt and Santalum album L, is a traditional and common prescription of Tibetan medicine. Tsantan Sumtang originates from Four Tantra with properties of nourishing heart and has been used as a folk medicine for cardiovascular diseases and heart failure in Qinghai, Tibet and Inner Mongolia. Our previous studies found that Tsantan Sumtang showed beneficial effects on right ventricular structure in hypoxia rats, while the underling mechanism remains unclear. To elucidate the underlying mechanisms of Tsantan Sumtang attenuated right ventricular (RV) remodeling and fibrosis of chronic hypoxia-induced pulmonary arterial hypertension (HPAH) rats. Fifty male Sprague Dawley (SD) rats (170 ± 20 g) were randomly divided into control group, hypoxia group, and hypoxia + Tsantan Sumtang groups (1.0 g· kg−1·day−1, 1.25 g· kg−1·day−1, 1.5 g ·kg−1·day−1). Rats in the hypoxia group and hypoxia + Tsantan Sumtang groups were maintained in a hypobaric chamber by adjusting the inner pressure and oxygen content to simulate an altitude of 4500 m for 28 days. The mean pulmonary arterial pressure (mPAP), right ventricle hypertrophy index (RVHI), the ratio of RV weight to tibia length (TL) (RV/TL), heart rate (HR) and RV systolic pressure (RVSP) was determined. Histomorphological assay of RV structure was evaluated by hematoxylin and eosin (HE) staining. RV tissue fibrosis was assessed by collagen proportion area (CPA), collagen I, collagen III and hydroxyproline content. CPA was obtained by picro-sirius red staining (PSR). The expression of collagen I and collagen III were detected by immunohistochemistry and western blotting. The hydroxyproline content was detected by alkaline hydrolysis. In addition, the level of angiotensin II (AngII) and angiotensin 1-7 (Ang1-7) in RV tissue was tested by enzyme-linked immune sorbent assay (ELISA). Protein expression of angiotensin-converting enzyme (ACE), AngII, AngII type 1 receptor (AT1R), angiotensin-converting enzyme 2 (ACE2), Mas receptor (Mas) were determined by immunohistochemistry and western blotting. mRNA level of ACE, AT1R, ACE2, Mas were tested by qPCR. The chemical profile of Tsantan Sumtang was revealed by UHPLC-Q-Exactive hybrid quadrupole-orbitrap mass analysis. Our results showed that RVHI, RV/TL and RVSP were significantly increased in HPAH rat. Furthermore, levels of collagen I, collagen III and hydroxyproline were up-regulated in RV tissue under hypoxia. We found that RV hypertrophy and fibrosis were associated with increased expression of ACE, AngII, AT1R as well as decreased expression of ACE2, Ang1-7 and Mas. RV remodeling and fibrosis were attenuated after Tsantan Sumtang administration by up-regulating ACE2 and Mas level as well as down-regulating ACE, AngII and AT1R levels in RV tissue. 35 constituents in Tsantan Sumtang were identified. Tsantan Sumtang attenuated RV remodeling and fibrosis in rat exposed to chronic hypoxia. The pharmacological effect of Tsantan Sumtang was based on equilibrating ACE-AngII-AT1R and ACE2-Ang1-7-Mas axis of RV tissue in HPAH rat. Image 1 [ABSTRACT FROM AUTHOR]