scholarly journals Nox2 Upregulation and p38α MAPK Activation in Right Ventricular Hypertrophy of Rats Exposed to Long-Term Chronic Intermittent Hypobaric Hypoxia

2020 ◽  
Vol 21 (22) ◽  
pp. 8576
Author(s):  
Eduardo Pena ◽  
Patricia Siques ◽  
Julio Brito ◽  
Silvia M. Arribas ◽  
Rainer Böger ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Nadph Oxidase ◽  
Right Ventricular ◽  
Hypobaric Hypoxia ◽  
Ventricular Hypertrophy ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Right Ventricular Hypertrophy ◽  
Mapk Activation ◽  
Intermittent Hypobaric Hypoxia

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.

scholarly journals Oxidative Stress, Kinase Activity and Inflammatory Implications in Right Ventricular Hypertrophy and Heart Failure under Hypobaric Hypoxia

2020 ◽  
Vol 21 (17) ◽  
pp. 6421
Author(s):  
Eduardo Pena ◽  
Julio Brito ◽  
Samia El Alam ◽  
Patricia Siques
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Right Ventricular ◽  
Hypobaric Hypoxia ◽  
Ventricular Hypertrophy ◽  
Current Knowledge ◽  
Right Heart Failure ◽  
Right Ventricular Hypertrophy ◽  
Therapeutic Approaches ◽  
Inflammatory Molecules

High altitude (hypobaric hypoxia) triggers several mechanisms to compensate for the decrease in oxygen bioavailability. One of them is pulmonary artery vasoconstriction and its subsequent pulmonary arterial remodeling. These changes can lead to pulmonary hypertension and the development of right ventricular hypertrophy (RVH), right heart failure (RHF) and, ultimately to death. The aim of this review is to describe the most recent molecular pathways involved in the above conditions under this type of hypobaric hypoxia, including oxidative stress, inflammation, protein kinases activation and fibrosis, and the current therapeutic approaches for these conditions. This review also includes the current knowledge of long-term chronic intermittent hypobaric hypoxia. Furthermore, this review highlights the signaling pathways related to oxidative stress (Nox-derived O2.- and H2O2), protein kinase (ERK5, p38α and PKCα) activation, inflammatory molecules (IL-1β, IL-6, TNF-α and NF-kB) and hypoxia condition (HIF-1α). On the other hand, recent therapeutic approaches have focused on abolishing hypoxia-induced RVH and RHF via attenuation of oxidative stress and inflammatory (IL-1β, MCP-1, SDF-1 and CXCR-4) pathways through phytotherapy and pharmacological trials. Nevertheless, further studies are necessary.

Alpha-skeletal actin messenger RNA increases in acute right ventricular hypertrophy

1990 ◽  
Vol 258 (4) ◽  
pp. L173-L178 ◽  
Author(s):  
P. R. Bakerman ◽  
K. R. Stenmark ◽  
J. H. Fisher
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Hypobaric Hypoxia ◽  
Ventricular Hypertrophy ◽  
Right Ventricular Hypertrophy ◽  
Hypoxic Exposure ◽  
Mrna Levels ◽  
Severe Pulmonary Hypertension ◽  
Cardiac Actin ◽  
Actin Mrna

Newborn calves exposed to hypobaric hypoxia develop severe pulmonary hypertension. Right ventricular hypertrophy and failure occur as a consequence of the increased pressure load. Alterations in right ventricular myocyte performance or differentiation could be reflected by the changes in the expression of contractile protein genes. We studied expression of contractile actin isotypes by measuring mRNA levels in total cellular RNA purified from right (RV) and left ventricles (LV) of calves with severe pulmonary hypertension after a 2-wk exposure to hypobaric hypoxia and age-matched controls. alpha-Skeletal actin mRNA was increased greater than 10-fold in the RV of hypertensive animals, whereas alpha-cardiac actin mRNA did not appear to change. alpha-Skeletal actin mRNA and alpha-cardiac actin mRNA did not increase in the LV of any of the hypoxic animals. After a 2-wk hypoxic exposure, calves were removed from the chamber. Two days later, RV alpha-skeletal actin mRNA decreased dramatically but was apparently elevated above that of an age-matched control. Thirty days after hypoxia, there appeared to be a persistent increase in RV alpha-skeletal actin mRNA. Although the physiological significance of these changes are unknown, an alteration in the RV myocyte phenotype has occurred.

E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats

1999 ◽  
Vol 277 (2) ◽  
pp. L225-L232 ◽  
Author(s):  
Norihisa Hanasato ◽  
Masahiko Oka ◽  
Masashi Muramatsu ◽  
Mayu Nishino ◽  
Hideyuki Adachi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cardiac Output ◽  
Arterial Pressure ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Systemic Arterial Pressure ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Arterial

The purpose of this study was to determine whether E-4010, a newly synthesized potent and selective orally active phosphodiesterase (PDE) 5 inhibitor, would prevent the development of chronic hypoxia-induced pulmonary hypertension in rats. In conscious, pulmonary hypertensive rats, a single oral administration of E-4010 (1.0 mg/kg) caused an acute, long-lasting reduction in mean pulmonary arterial pressure (PAP), with no significant effects on systemic arterial pressure, cardiac output, and heart rate. In rats that received food containing 0.01 or 0.1% E-4010 during the 3-wk exposure to hypoxia, mean PAP was significantly decreased (mean PAP 24.0 ± 0.9, 16.2 ± 0.8, and 12.8 ± 0.5 mmHg in rats treated with 0, 0.01, and 0.1% E-4010-containing food, respectively), whereas mean systemic arterial pressure was unchanged and cardiac output was slightly increased compared with chronically hypoxic control rats. Right ventricular hypertrophy, medial wall thickness in pulmonary arteries corresponding to the respiratory and terminal bronchioles, and the degree of muscularization of more distal arteries were less severe in E-4010-treated rats. Long-term treatment with E-4010 caused an increase in cGMP levels in lung tissue and plasma but not in aortic tissue and no significant change in cAMP levels in either lung, aorta, or plasma. These results suggest that long-term oral treatment with E-4010 reduced the increase in PAP, right ventricular hypertrophy, and pulmonary arterial remodeling induced by exposure to chronic hypoxia, probably through increasing cGMP levels in the pulmonary vascular smooth muscle.

Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy

2004 ◽  
Vol 286 (3) ◽  
pp. H1185-H1192 ◽  
Author(s):  
Saumya Sharma ◽  
Heinrich Taegtmeyer ◽  
Julia Adrogue ◽  
Peter Razeghi ◽  
Shiraj Sen ◽  
...  
Keyword(s):  
Right Ventricle ◽  
Right Ventricular ◽  
Pyruvate Dehydrogenase ◽  
Hypobaric Hypoxia ◽  
Ventricular Hypertrophy ◽  
Right Ventricular Hypertrophy ◽  
Pyruvate Dehydrogenase Kinase ◽  
Myosin Isoforms ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
The Right

Hypobaric hypoxia induces right ventricular hypertrophy. The relative contribution of pulmonary hypertension, decreased arterial oxygen, and neuroendocrine stimulation to the transcriptional profile of hypoxia-induced right ventricular hypertrophy is unknown. Whereas both ventricles are exposed to hypoxia and neuroendocrine stimulation, only the right ventricle is exposed to increased load. We postulated that right ventricular hypertrophy would reactivate the fetal gene transcriptional profile in response to increased load. We measured the expression of candidate genes in the right ventricle of rats exposed to hypobaric hypoxia (11% O2) and compared the results with the left ventricle. Hypoxia induced right ventricular hypertrophy without fibrosis. In the right ventricle only, atrial natriuretic factor transcript levels progressively increased starting at day 7. Metabolic genes were differentially regulated, suggesting a substrate switch from fatty acids to glucose during early hypoxia and a switch back to fatty acids by day 14. There was also a switch in myosin isogene expression and a downregulation of sarcoplasmic/endoplasmic ATPase 2a during early hypoxia, whereas later, both myosin isoforms and SERCA2a were upregulated. When the right and left ventricle were compared, the transcript levels of all genes, except for myosin isoforms and pyruvate dehydrogenase kinase-4, differed dramatically suggesting that all these genes are regulated by load. Our findings demonstrate that hypoxia-induced right ventricular hypertrophy transiently reactivates the fetal gene program. Furthermore, myosin iso-gene and pyruvate dehydrogenase kinase-4 expression is not affected by load, suggesting that either hypoxia itself or neuroendocrine stimulation is the primary regulator of these genes.

Resolution of Hypoxic Changes in the Heart and Pulmonary Arterioles of Rats during Intermittent Correction of Hypoxia

1977 ◽  
Vol 52 (2) ◽  
pp. 153-162 ◽  
Author(s):  
Enid Leach ◽  
P. Howard ◽  
R. Barer Gwenda
Keyword(s):  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Oxygen Therapy ◽  
Cor Pulmonale ◽  
Right Ventricular Hypertrophy ◽  
Airways Obstruction ◽  
Hypoxic Environment ◽  
Normal Environment

1. Rats kept in a hypoxic chamber (10% O2) for 3 or more weeks developed right ventricular hypertrophy, muscularization of pulmonary arterioles and polycythaemia. These changes resemble those found in human hypoxic disease and, in particular, in patients dying from chronic airways obstruction. 2. Resolution of these changes was studied in a normal environment and in an intermittently normal, intermittently hypoxic environment. The latter regimen modelled the situation of patients with cor pulmonale receiving long-term intermittent oxygen therapy. 3. In a normal environment right ventricular hypertrophy and polycythaemia were resolved in 6 weeks but vessel changes were not resolved in 12 weeks. 4. In the intermittently normoxic environment (40 or 80 h in air per week) there was some resolution of right ventricular hypertrophy in 6 weeks but no significant reduction in vessel thickening or in polycythaemia in 12 weeks.

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