Abstract
One of the consequences of high altitude (hypobaric hypoxia) exposure is the development of right ventricular hypertrophy (RVH). One particular type of exposure is long-term chronic intermittent hypobaric hypoxia (CIH); the molecular alterations in RVH in this particular condition are less known. Studies show an important role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex-induced oxidative stress and protein kinase activation in different models of cardiac hypertrophy. The aim was to determine the oxidative level, NADPH oxidase expression and MAPK activation in rats with RVH induced by CIH. Male Wistar rats were randomly subjected to CIH (2 days hypoxia/2 days normoxia; n = 10) and normoxia (NX; n = 10) for 30 days. Hypoxia was simulated with a hypobaric chamber. Measurements in the RV included the following: hypertrophy, Nox2, Nox4, p22phox, LOX-1 and HIF-1α expression, lipid peroxidation and H2O2 concentration, and p38α and Akt activation. All CIH rats developed RVH and showed an upregulation of LOX-1, Nox2 and p22phox and an increase in lipid peroxidation, HIF-1α stabilization and p38α activation. Rats with long-term CIH-induced RVH clearly showed Nox2, p22phox and LOX-1 upregulation and increased lipid peroxidation, HIF-1α stabilization and p38α activation. Therefore, these molecules may be considered new targets in CIH-induced RVH.
Highlights
Exposure of individuals to high altitude usually results in decreased oxygen bioavailability in blood and tissues [1].Altitude hypobaric hypoxia is classified according to the time of exposure, and there are three well-determined conditions: chronic hypobaric exposure, which represents people who live permanently at high altitude (Andes and Himalayas) [2] and acute exposure, which represents people who are exposed to high altitude for hours or few days
We explored some molecular pathways involved in right ventricular hypertrophy (RVH) under chronic intermittent hypobaric hypoxia (CIH) conditions
The results of this study show that exposure to CIH induces RVH concomitantly with increased lipid peroxidation, lipoprotein receptor-1 (LOX-1), Nox2, p22phox and hypoxia-inducible transcription factor-1α (HIF-1α) expression, and p38α MAPK activity
Summary
Exposure of individuals to high altitude usually results in decreased oxygen bioavailability in blood and tissues (hypobaric hypoxia) [1]. One important contributor to oxidative stress in the heart is the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex [20,27] It is composed of seven catalytic isoforms termed Nox to Nox and Duox1/2 [28]. Despite this difference regarding oxidative products, it has been reported that Nox and Nox upregulation is related to cardiac hypertrophy [29] This is supported by recent studies involving RVH induced by other models of hypoxia (normobaric hypoxia) showing an upregulation of Nox and Nox through the activation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) [20]. We hypothesized that Noxs (Nox2/4), p38αMAPK and Akt kinase, HIF-1α and LOX-1 would be overexpressed in CIH-induced RVH in rats, which we assessed in rats exposed to long-term CIH
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