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Transcriptomic Modifications in Developmental Cardiopulmonary Adaptations to Chronic Hypoxia Using a Murine Model of Simulated High Altitude Exposure

ABSTRACT: Mechanisms driving adaptive developmental responses to chronic high altitude (HA) exposure are incompletely known. We developed a novel rat model mimicking the human condition of cardiopulmonary adaptation to HA starting at conception and spanning the in utero and early life timeframe. We assessed lung growth and cardiopulmonary structure and function, and performed transcriptome analyses to identify mechanisms facilitating developmental adaptations to chronic hypoxia. To generate the model, breeding pairs of Sprague-Dawley rats were exposed to hypobaric hypoxia (equivalent to 9,000 feet elevation). Mating, pregnancy and delivery occurred in hypoxic conditions. Six weeks postpartum, structural and functional data were collected in the offspring. RNAseq was performed on right ventricle (RV) and lung tissue. Age-matched breeding pairs and offspring under room air (RA) conditions served as controls. Hypoxic rats exhibited significantly lower body weights and higher hematocrit levels, alveolar volumes, pulmonary diffusion capacities, RV mass, RV systolic pressure as well as increased pulmonary artery remodeling. RNAseq revealed multiple differentially expressed genes in lungs and RVs from hypoxic rats. While there was considerable similarity between hypoxic lungs and RVs compared to RA controls, several upstream regulators unique to lung or RV were identified. We noted a pattern of immune down-regulation and regulation patterns of immune and hormonal mediators similar to the genome from patients with pulmonary arterial hypertension. In summary, we developed a novel murine model of chronic hypoxia exposure that demonstrates functional and structural phenotypes similar to human adaptation. We identified transcriptomic alterations that suggest potential mechanisms for adaptation to chronic HA.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE140146 | GEO | 2020/09/30

REPOSITORIES: GEO

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Project description:Background: High-altitude hypoxia significantly impacts cardiovascular function, but the effects of adipose/metabolic factors on cardiovascular regulation remain unclear. Thus, a deeper understanding of adipose/metabolic factors’ role in cardiovascular function changes is needed. Methods: We assessed lung ventilation function, cardiovascular function, electrocardiogram, plasma CK-MB, sPecam-1, and 11 plasma adipose/metabolic factors in expeditioners at Antarctic Kunlun Station (4087m). To investigate adipose/metabolic factors’ effects and mechanisms on cardiac function, we constructed a rat model exposed to simulated hypobaric hypoxia (5000 m) with the same oxygen concentration as Kunlun Station. Echocardiography, ELISA, histology, and gene and protein expression studies were employed to examine cardiac function changes, pathological alterations, and leptin’s role in cardiac pathology under acute and chronic hypoxic exposure. Results: The Antarctic ice plateau environment significantly altered lung ventilation function, weakened cardiac pumping and contractile function, increased systematic vascular resistance (SVR), induced adaptive changes in cardiac conduction, significantly increased plasma CK-MB and Pecam-1, and significantly reduced plasma leptin, resistin, insulin, and lipocalin-2 levels. Decreased leptin was significantly correlated to cardiopulmonary function. Rats chronically exposed to simulated hypobaric hypoxia at 5000m exhibited pulmonary arterial hypertension (PAH), right ventricular hypertrophy (RVH), impaired left ventricular systolic and diastolic function, and significant deteriorated left ventricular global longitudinal strain (GLS), lateral and radial strains of the myocardium, with increased plasma CK-MB and sPecam-1 in hypoxic rats. Protein levels of leptin/ob-Rb, JAK2/STAT3, PI3K/AKT/GSK3β, and ERK/JNK were decreased in biventricular myocardial tissues of chronic hypoxia-exposed rats, accompanied by increased myocytes hypertrophy, fibrosis, lipid deposition, cell apoptosis, and mitochondrial dysfunction, and decreased metabolic gene levels. Left ventricular transcriptome analysis revealed that decreased myocardial leptin in hypoxic rats regulated cardiac pathology via down-regulated genes related to circadian rhythm, sodium/potassium ion transport, and cell skeleton. Conclusion: Our findings suggest that leptin is a crucial metabolic factor in regulating cardiac pathological changes and cardiac contractile and diastolic function under high altitudes. These regulatory pathways may involve leptin's classical signaling pathways and genes related to circadian rhythm, sodium/potassium ion transport, and cell skeleton in the heart.

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Transcriptomic Modifications in Developmental Cardiopulmonary Adaptations to Chronic Hypoxia Using a Murine Model of Simulated High Altitude Exposure

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