Generation of Oxidants by Hypoxic Human Pulmonary and Coronary Smooth-Muscle Cells (original) (raw)
Related papers
2007
Acute hypoxia causes pulmonary vasoconstriction and coronary vasodilation. The divergent effects of hypoxia on pulmonary and coronary vascular smooth muscle cells suggest that the mechanisms involved in oxygen sensing and downstream effectors are different in these two types of cells. Since production of reactive oxygen species (ROS) is regulated by oxygen tension, ROS have been hypothesized to be a signaling mechanism in hypoxia-induced pulmonary vasoconstriction and vascular remodeling. Furthermore, an increased ROS production is also implicated in arteriosclerosis. In this study, we determined and compared the effects of hypoxia on ROS levels in human pulmonary arterial smooth muscle cells (PASMC) and coronary arterial smooth muscle cells (CASMC). Our results indicated that acute exposure to hypoxia (PO 2 =25-30 mmHg for 5-10 min) significantly and rapidly decreased ROS levels in both PASMC and CASMC.
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.
AJP: Lung Cellular and Molecular Physiology, 2003
At birth, associated with the rise in oxygen tension, the pulmonary arteries (PA) dilate and the ductus arteriosus (DA) constricts. Both PA and DA constrict with vasoconstrictors and dilate with vasodilators. They only respond in a contrary manner to changes in oxygen tension. We have hypothesized that the effects of changes in oxygen are mediated by changes in redox status. Consequently, we tested whether a reducing agent dithiothreitol (DTT), and an oxidizing agent, dithionitrobenzoicacid (DTNB) would have opposite effects on a major oxygen signalling pathway in the PA and DA smooth muscle cells (SMCs); the sequence of change in potassium current (Ik), membrane potential, cytosolic calcium and vessel tone. Under normoxic conditions DTT constricted adult and fetal resistance PA rings, while in DA rings DTT acted as a potent vasodilator. In normoxia voltage clamp measurements showed inhibition of Ik by DTT in PASMCs and in contrast, activation in DASMCs. Consequently, DTT depolarized the fetal and adult PASMCs and hyperpolarized DASMCs. Intracellular [Ca2+] was increased by DTT in fetal and adult PASMCs and decreased in DASMCs. Under hypoxic conditions the oxidizing agent DTNB constricted DA rings and caused vasodilatation in fetal PA rings. DTNB inhibited Ik and depolarized the cell membrane in DASMCs. In contrast, activation of Ik and hyperpolarization were seen in PASMCs. Thus, the same redox signal can elicit opposite effects on potassium current, membrane potential, cytosolic calcium and vascular tone in the resistance PA and in the DA. These observations support the concept that redox changes could signal the opposite effects of oxygen in the PA and DA.
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.
Oxidative Stress in Hypobaric Hypoxia and Influence on Vessel-Tone Modifying Mediators
High Altitude Medicine & Biology, 2013
Oxidative stress in hypobaric hypoxia and influence on vessel-tone modifying mediators. High Alt Med Biol. 14:273-279, 2013.-Increased pulmonary artery pressure is a well-known phenomenon of hypoxia and is seen in patients with chronic pulmonary diseases, and also in mountaineers on high altitude expedition. Different mediators are known to regulate pulmonary artery vessel tone. However, exact mechanisms are not fully understood and a multimodal process consisting of a whole panel of mediators is supposed to cause pulmonary artery vasoconstriction. We hypothesized that increased hypoxemia is associated with an increase in vasoconstrictive mediators and decrease of vasodilatators leading to a vasoconstrictive net effect. Furthermore, we suggested oxidative stress being partly involved in changement of these parameters. Oxygen saturation (Sao 2) and clinical parameters were assessed in 34 volunteers before and during a Swiss research expedition to Mount Muztagh Ata (7549 m) in Western China. Blood samples were taken at four different sites up to an altitude of 6865 m. A mass spectrometry-based targeted metabolomic platform was used to detect multiple parameters, and revealed functional impairment of enzymes that require oxidation-sensitive cofactors. Specifically, the tetrahydrobiopterin (BH4)-dependent enzyme nitric oxide synthase (NOS) showed significantly lower activities (citrulline-to-arginine ratio decreased from baseline median 0.21 to 0.14 at 6265 m), indicating lower NO availability resulting in less vasodilatative activity. Correspondingly, an increase in systemic oxidative stress was found with a significant increase of the percentage of methionine sulfoxide from a median 6% under normoxic condition to a median level of 30% (p < 0.001) in camp 1 at 5533 m. Furthermore, significant increase in vasoconstrictive mediators (e.g., tryptophan, serotonin, and peroxidation-sensitive lipids) were found. During ascent up to 6865 m, significant altitude-dependent changes in multiple vessel-tone modifying mediators with excess in vasoconstrictive metabolites could be demonstrated. These changes, as well as highly significant increase in systemic oxidative stress, may be predictive for increase in acute mountain sickness score and changes in Sao 2 .
Editorial – Hypoxia and reoxygenation: from basic science to bedside
A condition with inadequate oxygen supply to the tissues, hypoxia plays a pivotal role in the pathology of cyanotic congenital heart defects and several adult diseases as myocardial infarction, stroke, cancer, diabetes, aging, and pulmonary obstruction. Most cell responses to hypoxia are modulated by hypoxia-inducible factors [HIFs (1)], DNA-binding transcription factors that mediate hypoxia adaptation through activation of a multitude of genes encoding proteins needed to improve tissue oxygen delivery, energy metabolism, efficient management of hypoxia-induced stress and regulation of apoptosis, autophagy, and cell cycle. The reoxygenation that follows hypoxia usually induces bursts of reactive oxygen species, which not only cause the oxidative damage central in the pathophysiology of hypoxia/reoxygenation (HReox) injury but also activate signaling mechanisms that in part synergize and in part oppose those induced by hypoxia. Consequently, it becomes often difficult to distinguish what is attributable to hypoxia and what to the reoxygenation that follows hypoxia. A new research frontier may foster clues to understand the mechanisms underlying HReox injury and to identify appropriate targets to design interventions aimed at reducing the toll of this injury in several diseases.
Chronic hypoxia induces Rho kinase-dependent myogenic tone in small pulmonary arteries
AJP: Lung Cellular and Molecular Physiology, 2008
Myogenic tone in the pulmonary vasculature of normoxic adult animals is minimal or nonexistent. Whereas chronic hypoxia (CH) increases basal tone in pulmonary arteries, it is unclear if a portion of this elevated tone is due to development of myogenicity. Since basal arterial RhoA activity and Rho kinase (ROK) expression are augmented by CH, we hypothesized that CH elicits myogenic reactivity in pulmonary arteries through ROK-dependent vascular smooth muscle (VSM) Ca2+ sensitization. To test this hypothesis, we assessed the contribution of ROK to basal tone and pressure-induced vasoconstriction in endothelium-disrupted pulmonary arteries [50–300 μm inner diameter (ID)] from control and CH [4 wk at 0.5 atmosphere (atm)] rats. Arteries were loaded with fura-2 AM to continuously monitor VSM intracellular Ca2+ concentration ([Ca2+]i). Basal VSM [Ca2+]i was not different between groups. The ROK inhibitor, HA-1077 (100 nM to 30 μM), caused a concentration-dependent reduction of basal tone...
Modulation of hypoxic pulmonary vasoconstriction by antioxidant enzymes in red blood cells
American Journal of Respiratory and Critical Care Medicine, 1996
To determine whether antioxidant mechanisms within red blood cells (RBCs) significantly contribute to preserving hypoxic pulmonary vasoconstriction (HPV) in both the absence and the presence of oxidative stress, we investigated HPV changes in isolated rabbit lungs perfused with solutions containing RBCs treated with various inhibitors of superoxide dismutase (SOD), anion channels, catalase (CAT), or glutathione peroxidase (GSH-Px). Perfusion was maintained at a constant flow rate of 70 ml/min, and lung temperature at 37 to 38 0 C. Hematocrit was adjusted to 7%. In the absence of overt oxidative stress, HPV was significantly enhanced in the perfusate containing control RBCs (untreated RBCs) as compared with that in Krebs-Henseleit buffer. Inhibition of SOD, CAT, and GSH-Px within RBCs, as well as anion channels located on the RBC membrane, had little influence on HPV. Neither exogenous SOD nor CAT altered HPV. In the presence of high levels of reactive oxygen species (ROS), generated by addition of xanthine (100 liM) and xanthine oxidase (10 mU/ml) to the reservoir, HPV was considerably suppressed in the perfusate containing only buffer but was restored in the perfusate with control RBCs. Inhibition of CAT or GSH-Px in RBCs preserved the HPV, whereas inhibition of SOD or anion channels failed to preserve HPV obtained during exposure to high ROS levels. Addition of exogenous SOD, but not CAT, to the perfusate containing RBCs in which endogenous SOD had been inhibited restored HPV under high ROS conditions. In conclusion, (1) although RBCs augment HPV in the absence of ROS, this finding is not attributable to the antioxidants in RBCs. (2) RBCs restore HPV upon exposure to high ROS. This finding may well be explained by antioxidant mechanisms operating within RBCs, especially those of endogenous SOD.