Oxidative Stress, Kinase Activity and Inflammatory Implications in Right Ventricular Hypertrophy and Heart Failure under Hypobaric Hypoxia (original) (raw)
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Frontiers in Physiology, 2021
High-altitude exposure results in hypobaric hypoxia, which affects organisms by activating several mechanisms at the physiological, cellular, and molecular levels and triggering the development of several pathologies. One such pathology is high-altitude pulmonary hypertension (HAPH), which is initiated through hypoxic pulmonary vasoconstriction to distribute blood to more adequately ventilated areas of the lungs. Importantly, all layers of the pulmonary artery (adventitia, smooth muscle, and endothelium) contribute to or are involved in the development of HAPH. However, the principal action sites of HAPH are pulmonary artery smooth muscle cells (PASMCs), which interact with several extracellular and intracellular molecules and participate in mechanisms leading to proliferation, apoptosis, and fibrosis. This review summarizes the alterations in molecular pathways related to oxidative stress, inflammation, kinase activation, and other processes that occur in PASMCs during pulmonary hy...
International Journal of Molecular Sciences
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 dev...
Reactive Oxygen Species at High Altitude (Hypobaric Hypoxia) on the Cardiovascular System
Reactive Oxygen Species (ROS) in Living Cells
Reactive oxygen species (ROSs) play important physiological and physiopathological roles in the cardiovascular system. An imbalance between ROS and antioxidants, termed oxidative stress, can contribute to endothelial dysfunction and cardiovascular remodeling. ROSs have been demonstrated to be increased and to regulate the following main pulmonary vasculature changes that occur at high altitude (hypobaric hypoxia): hypoxic pulmonary vasoconstriction (HPV), pulmonary hypertension, right ventricular hypertrophy (RVH), and ultimately, cardiac failure. Thus, ROS increases are a public health concern for the increasing number of people living or working at high altitudes. ROSs trigger the activation of different metabolic signaling pathways that alter the activity of redox-sensitive transcription factors and translational signals. Consequently, we provide a comprehensive review of the literature on the main factors, sources, and mechanisms of action of ROS and their effects on the cardiovascular system under hypobaric hypoxic conditions. Although ROS generation is a normal physiological activity, under hypobaric hypoxia (high altitude) conditions, ROS levels are elevated. The principal sources of ROS are nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-4 (NOX4) in the vascular system and NOX2 in cardiac tissue. Thus, the information presented in this review provides a broad view of the relationship between ROS and hypoxia.
Role of Oxidative Stress and NFkB In Hypoxia-Induced Pulmonary Edema
… biology and medicine, 2008
Hypoxia is well known to increase the free radical generation in the body, leading to oxidative stress. In the present study, we have determined whether the increased oxidative stress further upregulates the nuclear transcription factor (NFkB) in the development of pulmonary ...
Reactive oxygen species (ROSs) play important physiological and physiopathological roles in the cardiovascular system. An imbalance between ROS and antioxidants, termed oxidative stress, can contribute to endothelial dysfunction and cardiovascular remodel-ing. ROSs have been demonstrated to be increased and to regulate the following main pulmonary vasculature changes that occur at high altitude (hypobaric hypoxia): hypoxic pulmonary vasoconstriction (HPV), pulmonary hypertension, right ventricular hyper-trophy (RVH), and ultimately, cardiac failure. Thus, ROS increases are a public health concern for the increasing number of people living or working at high altitudes. ROSs trigger the activation of different metabolic signaling pathways that alter the activity of redox-sensitive transcription factors and translational signals. Consequently, we provide a comprehensive review of the literature on the main factors, sources, and mechanisms of action of ROS and their effects on the cardiovascular system under hypobaric hypoxic conditions. Although ROS generation is a normal physiological activity, under hypo-baric hypoxia (high altitude) conditions, ROS levels are elevated. The principal sources of ROS are nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-4 (NOX4) in the vascular system and NOX2 in cardiac tissue. Thus, the information presented in this review provides a broad view of the relationship between ROS and hypoxia.
2012
We evaluated the left ventricle (LV) response to hypoxia by comparing male Sprague Dawley rats exposed for 7 days to normoxia (control, n ¼ 18), chronic sustained hypoxia (CSH; n ¼ 12) and chronic intermittent hypoxia (CIH; n ¼ 12). Out of the 168 inflammatory, extracellular matrix and adhesion molecule genes evaluated, Ltb, Cdh4, Col5a1, Ecm1, MMP-11 and TIMP-2 increased in the LV (range: 87-138%), whereas Tnfrsf1a decreased 27%, indicating an increase in inflammatory status with CSH (all Po0.05). CIH decreased Ltb, Spp1 and Ccl5 levels, indicating reduced inflammatory status. While Laminin b2 gene Q3 levels increased 123%, MMP-9 and fibronectin gene levels both decreased 74% in CIH (all Po0.05). Right ventricle/body weight ratios increased in CSH (1.1þ0.1 g g À1 ) compared with control (0.7þ0.1 g g À1 ) and CIH (0.8þ0.1 g g À1 ; both Po0.05). Lung to body weight increased in CSH, while LV/body weight ratios were similar among all three groups. With CIH, myocyte cross sectional areas increased 25% and perivascular fibrosis increased 100% (both Po0.05). Gene changes were independent of global changes and were validated by protein levels. MMP-9 protein levels decreased 94% and fibronectin protein levels decreased 42% in CIH (both Po0.05). Consistent with a decreased inflammatory status, HIF-2a and eNOS protein levels were 36% and 44% decreased, respectively, in CIH (both Po0.05). In conclusion, our results indicate that following 7 days of hypoxia, inflammation increases in response to CSH and decreases in response to CIH. This report is the first to demonstrate specific and differential changes seen in the LV during chronic sustained and CIH.
Reactive Oxygen Species and Pulmonary Vasculature During Hypobaric Hypoxia
An increasing number of people are living or working at high altitudes (hypobaric hypoxia) and therefore suffering several physiological, biochemical, and molecular changes. Pulmonary vasculature is one of the main and first responses to hypoxia. These responses imply hypoxic pulmonary vasoconstriction (HPV), remodeling, and eventually pulmonary hypertension (PH). These events occur according to the type and extension of the exposure. There is also increasing evidence that these changes in the pulmonary vascular bed could be mainly attributed to a homeostatic imbalance as a result of increased levels of reactive oxygen species (ROS). The increase in ROS production during hypobaric hypoxia has been attributed to an enhanced activity and expression of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), though there is some dispute about which subunit is involved. This enzymatic complex may be directly induced by hypoxia-inducible factor-1α (HIF-1α). ROS has been found to be related to several pathways, cells, enzymes, and molecules in hypoxic pulmonary vasculature responses, from HPV to inflammation, and structural changes, such as remodeling and, ultimately, PH. Therefore, we performed a comprehensive review of the current evidence on the role of ROS in the development of pulmonary vasculature changes under hypoxic conditions, with a focus on hypobaric hypoxia. This review provides information supporting the role of oxidative stress (mainly ROS) in the pulmonary vasculature's responses under hypobaric hypoxia and depicting possible future therapeutics or research targets. NADPH oxidase-produced oxidative stress is highlighted as a major source of ROS. Moreover, new molecules, such as asymmetric dimethylarginine, and critical inflammatory cells as fibroblasts, could be also involved. Several controversies remain regarding the role of ROS and the mechanisms involved in hypoxic responses that need to be elucidated.
Acta Physiologica, 2010
Protein kinase C (PKC), cloned as a serine/threonine kinase, plays key roles in diverse intracellular signalling processes and in cardiovascular remodelling during pressure overload or volume overload. We looked for correlations between changes in PKC isoforms (levels and/or subcellular distributions) and cardiac remodelling during experimental hypobaric hypoxic environment (HHE)-induced pulmonary hypertension. Methods: To study the PKC system in the heart during HHE, 148 male Wistar rats were housed for up to 21 days in a chamber at the equivalent of 5500 m altitude level (10% O 2). Results: At 14 or more days of exposure to HHE, pulmonary arterial pressure (PAP) was significantly increased. In the right ventricle (RV): (1) the expression of PKC-a protein in the cytosolic and membrane fractions was increased at 3-14 days and at 5-7 days of exposure respectively; (ii) the cytosolic expression of PKC-d protein was increased at 1-5, 14 and 21 days of exposure; (3) the membrane expressions of the proteins were decreased at 14-21 (PKC-bII), 14-21 (PKC-c), and 0.5-5 and 21 (PKC-) days of exposure; (4) the expression of the active form of PKC-a protein on the plasma membrane was increased at 3 days of exposure (based on semiquantitative analysis of the immunohistochemistry). In the left ventricle, the expressions of the PKC mRNAs, and of their cytosolic and membrane proteins, were almost unchanged. The above changes in PKC-a, which were strongly evident in the RV, occurred alongside the increase in PAP. Conclusion: PKC-a may help to modulate the right ventricular hypertrophy caused by pulmonary hypertension in HHE. Keywords gene expression, heart, hypobaric hypoxia, protein kinase C.