Cardiac Acclimatization at High Altitude in Two Different Ethnicity Groups.

Gaur, Priya, Meerim Sartmyrzaeva, Abdirashit Maripov, Kubatbek Muratali Uulu, Supriya Saini, Koushik Ray, Krishna Kishore, Almaz Akunov, Akpay Sarybaev, Bhuvnesh Kumar, Shashi Bala Singh, and Praveen Vats. Cardiac acclimatization at high altitude in two different ethnicity groups. High Alt Med Biol. 22:58-69, 2021. Introduction: High altitude (HA) exposure causes substantial increase in pulmonary artery pressure (PAP) and resistance. However, the effects of HA hypoxia exposure on cardiac function remain incompletely understood. Studies evaluating interethnic differences in cardiac functions in response to HA exposure are lacking. We aimed to compare the cardiac performance in Indian versus Kyrgyz healthy lowland subjects over the course of a 3-week HA exposure at 4,111 m. Methodology: Ten Indians and 20 Kyrgyz subjects were studied to assess cardiac acclimatization noninvasively by echocardiography in two different ethnic groups for 3 weeks of stay at HA. Pulmonary hemodynamics, right and left ventricular functions were evaluated at basal and on days 3, 7, 14, and 21 of HA exposure and on day 3 of deinduction. Results: HA exposure significantly increased PAP, pulmonary vascular resistance, cardiac output (CO), and heart rates (HRs) in both groups. Tricuspid regurgitant gradient increased significantly in both the group at day 3 versus basal; 38.9 mmHg (31.8, 42.9) versus 21.9 mmHg (19.5, 22.6) in Kyrgyz; and 34.1 mmHg (30.2, 38.5) versus 20.4 mmHg (19.7, 21.3) in Indians. HR increased significantly in Indians at day 3 and 7, whereas in Kyrgyz throughout exposure. CO increased significantly in both groups at day 3 versus basal with 5.9 L/min (5.5, 6.4) versus 5.1 L/min (4.4, 5.9) in Kyrgyz, and 5.7 L/min (5.56, 5.98) versus 4.9 L/min (4.1, 5.3) in Indians. Both groups exhibited preserved right ventricular diastolic and systolic functions at HAs. HA exposure changed the left ventricular diastolic parameters only in Kyrgyz subjects with impaired mitral inflow E/A, but not in Indian subjects. All cardiac changes induced at HAs have been recovered fully upon deinduction in both, except lateral-septal A', which remained low in Indians. Conclusion: Although pulmonary hemodynamics responses were similar in both groups, there were differences in cardiac functional parameters between the two in response to HA exposure that may be accounted to ethnic variation.

Temporal transcriptome analysis suggest modulation of multiple pathways and gene network involved in cell-cell interaction during early phase of high altitude exposure.

High altitude (HA) conditions induce several physiological and molecular changes, prevalent in individuals who are unexposed to this environment. Individuals exposed towards HA hypoxia yields physiological and molecular orchestration to maintain adequate tissue oxygen delivery and supply at altitude. This study aimed to understand the temporal changes at altitude of 4,111m. Physiological parameters and transcriptome study was conducted at high altitude day 3, 7, 14 and 21. We observed changes in differentially expressed gene (DEG) at high altitude time points along with altered BP, HR, SpO2, mPAP. Physiological changes and unsupervised learning of DEG's discloses high altitude day 3 as distinct time point. Gene enrichment analysis of ontologies and pathways indicate cellular dynamics and immune response involvement in early day exposure and later stable response. Major clustering of genes involved in cellular dynamics deployed into broad categories: cell-cell interaction, blood signaling, coagulation system, and cellular process. Our data reveals genes and pathways perturbed for conditions like vascular remodeling, cellular homeostasis. In this study we found the nodal point of the gene interactive network and candidate gene controlling many cellular interactive pathways VIM, CORO1A, CD37, STMN1, RHOC, PDE7B, NELL1, NRP1 and TAGLN and the most significant among them i.e. VIM gene was identified as top hub gene. This study suggests a unique physiological and molecular perturbation likely to play a critical role in high altitude associated pathophysiological condition during early exposure compared to later time points.

Global expression profiling and pathway analysis in two different population groups in relation to high altitude.

High altitude (HA) is associated with number of stresses. Response of these stresses may vary in different populations depending upon altitude, duration of residency, ancestry, geographical variation, lifestyle, and ethnicities. For understanding population variability in transcriptome, array-based global gene expression profiling was performed on extracted RNA of male volunteers of two different lowland population groups, i.e., Indians and Kyrgyz, at baseline and day 7 of HA exposure (3200 m). A total of 97 genes were differentially expressed at basal in Kyrgyz as compared to Indians (82 downregulated and 15 upregulated), and 196 were differentially expressed on day 7 of HA (118 downregulated and 78 upregulated). Ingenuity Pathway Analysis and gene ontology highlighted eIF2 signaling with most significant negative activation z score at basal in Kyrgyz compared to Indians with downregulation of various L- and S-ribosomal proteins indicating marked translational repression. On day 7, cAMP-mediated signaling is most enriched with positive activation z score in Kyrgyz compared to Indians. Plasma cAMP levels were higher in Kyrgyz on day 7 compared to Indians. Extracellular adenosine levels were elevated in both the groups upon HA, but higher in Kyrgyz compared to Indians. Valedictory qRT-PCR showed upregulation of ADORA2B and CD73 along with downregulation of ENTs in Kyrgyz compared to Indians indicating elevated levels of extracellular nucleotides mainly adenosine and activation of extracellular cAMP-adenosine pathway which as per literature triggers endogenous protective mechanisms under stress conditions like hypoxia. Thus, transcriptome changes at HA are population-specific, and it may be necessary to take care while interposing similar results in different populations.

Regulation, signalling and functions of hormonal peptides in pulmonary vascular remodelling during hypoxia.

Hypoxic state affects organism primarily by decreasing the amount of oxygen reaching the cells and tissues. To adjust with changing environment organism undergoes mechanisms which are necessary for acclimatization to hypoxic stress. Pulmonary vascular remodelling is one such mechanism controlled by hormonal peptides present in blood circulation for acclimatization. Activation of peptides regulates constriction and relaxation of blood vessels of pulmonary and systemic circulation. Thus, understanding of vascular tone maintenance and hypoxic pulmonary vasoconstriction like pathophysiological condition during hypoxia is of prime importance. Endothelin-1 (ET-1), atrial natriuretic peptide (ANP), and renin angiotensin system (RAS) function, their receptor functioning and signalling during hypoxia in different body parts point them as disease markers. In vivo and in vitro studies have helped understanding the mechanism of hormonal peptides for better acclimatization to hypoxic stress and interventions for better management of vascular remodelling in different models like cell, rat, and human is discussed in this review.

PRMT1 promotes hyperglycemia in a FoxO1-dependent manner, affecting glucose metabolism, during hypobaric hypoxia exposure, in rat model.

PURPOSE: High-altitude (HA) environment causes changes in cellular metabolism among unacclimatized humans. Previous studies have revealed that insulin-dependent activation of protein kinase B (Akt) regulates metabolic processes via discrete transcriptional effectors. Moreover, protein arginine methyltransferase (PRMT)1-dependent arginine modification of forkhead box other (FoxO)1 protein interferes with Akt-dependent phosphorylation. The present study was undertaken to test the involvement of PRMT1 on FoxO1 activation during hypobaric hypoxia (HH) exposure in rat model. METHODS: Samples were obtained from normoxia control (NC) and HH-exposed (H) rats, subdivided according to the duration of HH exposure. To explore the specific role played by PRMT1 during HH exposure, samples from 1d pair-fed (PF) NC, 1d acute hypoxia-exposed (AH) placebo-treated, and 1d AH TC-E-5003-treated rats were investigated. Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) was performed to determine expressions of glycolytic, gluconeogenic enzymes, and insulin response regulating genes. Immuno-blot and enzyme linked immunosorbent assay (ELISA) were used for insulin response regulating proteins. Nuclear translocation of FoxO1 was analyzed using deoxyribonucleic acid (DNA)-binding ELISA kit. RESULTS: We observed HH-induced increase in glycolytic enzyme expressions in hepatic tissue unlike hypothalamic tissue. PRMT1 expression increased during HH exposure, causing insulin resistance and resulting increase in FoxO1 nuclear translocation, leading to hyperglycemia. Conversely, PRMT1 inhibitor treatment promoted inhibition of FoxO1 activity and increase in glucose uptake during HH exposure leading to reduction in blood-glucose and hepatic glycogen levels. CONCLUSIONS: PRMT1 might have a potential importance as a therapeutic target for the treatment of HH-induced maladies.

Changes in ghrelin, CCK, GLP-1, and peroxisome proliferator-activated receptors in a hypoxia-induced anorexia rat model.

INTRODUCTION: A high-altitude environment causes appetite loss in unacclimatised humans, leading to weight reduction. Ghrelin, cholecystokinin (CCK), and glucagon like peptide-1 (GLP-1), are gut hormones involved in the regulation of food intake and energy metabolism. The liver is an important site of metabolic regulation, and together with the gut it plays a role in food intake regulation. This study intends to study the time-dependent changes occurring in plasma gut hormones, PPARα, PPARδ, and PGC1α, in the stomach and liver during hypoxia. MATERIAL AND METHODS: Male Sprague Dawley rats were exposed to hypobaric hypoxia in a decompression chamber at 7620 m for different durations up to seven days. RESULTS: Hypoxia increased circulating ghrelin from the third day onwards while CCK and GLP-1 decreased immediately. An increase in ghrelin, ghrelin receptor protein levels, and GOAT mRNA levels in the stomach was observed. Stomach cholecystokinin receptor (CCKAR), PPARα, and PPARδ decreased. Liver CCKAR decreased during the first day of hypoxia and returned to normal levels from the third day onwards. PPARα and PGC1α expression increased while PPARδ protein levels reduced in the liver on third day. CONCLUSION: Hypoxia alters the expression of ghrelin and ghrelin receptor in the stomach, CCKAR in the liver, and PPAR and its cofactors, which might be possible role players in the contribution of gut and liver to anorexia at high altitude.

Role of BMP7 in appetite regulation, adipogenesis, and energy expenditure.

Bone morphogenetic protein 7 (BMP7), also known as osteogenic protein-1 (OP-1) is a member of Transforming growth factor-ß (TGF-ß) family of proteins. Bone morphogenetic proteins were discovered in 1965 by Marshal Urist, of which BMP7 is of particular interest in this review being a leptin-independent anorexinogen and having role in energy expenditure in the brown adipose tissue, which makes it a potential target for preventing/treating obesity. As it has been established that Obesity displays a state of leptin-resistance, thus a protein-like BMP7 which acts through a leptin-independent pathway could give new therapeutic directions. This review will also discuss the synthesis and action of BMP7, along with its receptors and signal transduction. A brief note about BMP7-mediated brown fat development and energy balance is also discussed.