Chronic Hypobaric Hypoxia Induces Right Ventricular Hypertrophy and Apoptosis in Rats: Therapeutic Potential of Nanocurcumin in Improving Adaptation

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.

Download Full-text

Effect of hypobaric hypoxia and diet on blood parameters and pulmonary hypertension‐induced right ventricular hypertrophy in turkey poults and ducklings

Avian Pathology ◽

10.1080/03079459308418956 ◽

1993 ◽

Vol 22 (4) ◽

pp. 683-692 ◽

Cited By ~ 2

Author(s):

R. J. Julian ◽

S. M. Mirsalimi ◽

E. J. Squires

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Hypobaric Hypoxia ◽

Ventricular Hypertrophy ◽

Blood Parameters ◽

Right Ventricular Hypertrophy ◽

Turkey Poults

Download Full-text

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1990.258.4.l173 ◽

1990 ◽

Vol 258 (4) ◽

pp. L173-L178 ◽

Cited By ~ 1

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.

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms21228576 ◽

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.

Download Full-text

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00916.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. H1185-H1192 ◽

Cited By ~ 55

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.

Download Full-text