Nox2 Upregulation and p38α MAPK Activation in Right Ventricular Hypertrophy of Rats Exposed to Long-Term Chronic Intermittent Hypobaric Hypoxia (original) (raw)
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International Journal of Molecular Sciences
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 hypox...
Induction of Cardiac Nitric Oxide Synthase 2 in Rats Exposed to Chronic Hypoxia
Journal of Molecular and Cellular Cardiology, 1999
Induction of nitric oxide synthase (NOS2, also designated as iNOS) in the heart is known to occur in response to various stimuli. It is not known, however, whether in vivo hypoxia leads to cardiac NOS2 induction. We thus investigated the effects of normobaric hypoxia (10% O 2 for 8, 15 and 21 days) on NOS2 protein expression and enzyme activity in rat right ventricle (RV) and left ventricle (LV). Chronic hypoxia induced RV hypertrophy: the RV weight to body weight ratio was increased by 45% upon 15 days of exposure, with no change thereafter and no change in left ventricular (LV) weight. Treatment of hypoxic rats with -NAME for 1 month decreased pulmonary artery pressure and RV hypertrophy compared to hypoxic non-treated rats. NOS2 activity detected by [ 3 H] -arginine to [ 3 H] -citrulline conversion increased in RV during hypoxia, with a maximum at 15 days (+161% of control rats; P<0.05), whereas it increased less (by 60%) in LV. In parallel, after 15 days of hypoxia there was a three-fold increase in NOS2 protein abundance detected by Western blotting using an isoform-specific antibody in the RVs (two-fold increase in the LV). Immunochemistry with the specific antibody demonstrated the expression in cardiomyocytes isolated from both ventricles of normoxic and hypoxic rats. Protein kinase C (PKC) content and activity was unchanged in LV of hypoxic rats, but increased in RV as compared with normoxic rats. These results clearly show that, in the heart, NOS2 is upregulated by hypoxia with an expression in cardiomyocytes of both ventricles. In addition, NOS2 is more inducible in the right hypertrophied ventricle than in the left non-hypertrophied hypoxic ventricle.
Cardioprotection after acute exposure to simulated high altitude in rats. Role of nitric oxide
Nitric oxide : biology and chemistry, 2017
In previous studies, upregulation of NOS during acclimatization of rats to sustained hypobaric hypoxia was associated to cardioprotection, evaluated as an increased tolerance of myocardium to hypoxia/reoxygenation. The objective of the present work was to investigate the effect of acute hypobaric hypoxia and the role of endogenous NO concerning cardiac tolerance to hypoxia/reoxygenation under β-adrenergic stimulation. Rats were submitted to 58.7 kPa in a hypopressure chamber for 48 h whereas their normoxic controls remained at 101.3 kPa. By adding NOS substrate L-arg, or blocker L-NNA, isometric mechanical activity of papillary muscles isolated from left ventricle was evaluated at maximal or minimal production of NO, respectively, under β-adrenergic stimulation by isoproterenol, followed by 60/30 min of hypoxia/reoxygenation. Activities of NOS and cytochrome oxidase were evaluated by spectrophotometric methods and expression of HIF1-α and NOS isoforms by western blot. Eosin and hema...
Journal of Applied Physiology, 2008
Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality. We have reported that chronic intermittent hypoxia (CIH), a direct consequence during OSA, leads to left ventricular (LV) remodeling and dysfunction in rats. The present study is to determine LV myocardial cellular injury that is possibly associated with LV global dysfunction. Fifty-six rats were exposed either to CIH (nadir O2 4–5%) or sham (handled normoxic controls, HC), 8 h/day for 6 wk. At the end of the exposure, we studied LV global function by cardiac catheterization, and LV myocardial cellular injury by in vitro analyses. Compared with HC, CIH animals demonstrated elevations in mean arterial pressure and LV end-diastolic pressure, but reductions in cardiac output (CIH 141.3 ± 33.1 vs. HC 184.4 ± 21.2 ml·min−1·kg−1, P < 0.01), maximal rate of LV pressure rise in systole (+dP/d t), and maximal rate of LV pressure fall in diastole (−dP/d t). CIH led to significant cell injury in the left myocard...
Oxidative Stress and Left Ventricular Function with Chronic Intermittent Hypoxia in Rats
American Journal of Respiratory and Critical Care Medicine, 2005
Rationale and Objectives: Obstructive sleep apnea (OSA) is associated with oxidative stress and myocardial dysfunction. We hypothesized that the chronic intermittent hypoxia (CIH) component of OSA is sufficient to lead to these adverse effects. Methods and Results: Rats were exposed to CIH (nadir O 2 , 4-5%) for 8 hours/day, 5 days/week, for 5 weeks. Results were compared with similarly handled controls (HC). Outcomes included blood pressure (tail cuff plethysmograph), echocardiographic and invasive measures of left-ventricular (LV) function, and indices of oxidative stress that included levels of myocardial lipid peroxides and Cu/Zn superoxide dismutase. Blood pressure was greater in CIH (n ϭ 22) than in HC (n ϭ 22) after 2 weeks of exposure (136 Ϯ 12 vs. 128 Ϯ 8 mm Hg; p Ͻ 0.05). However, the difference disappeared by 5 weeks (127 Ϯ 13 vs. 127 Ϯ 13 mm Hg). LV weight/heart weight was greater with CIH (CIH, 0.52 Ϯ 0.05; HC, 0.47 Ϯ 0.06; p Ͻ 0.005). Echocardiograms revealed LV dilation, as well as decreased LV fractional shortening (CIH, 29.7 Ϯ 9.8%; HC, 37.4 Ϯ 7.1%; p Ͻ 0.001). LV end-diastolic pressure was increased with CIH (CIH, 13.7 Ϯ 5.5; HC, 8.0 Ϯ 2.9 mm Hg; p Ͻ 0.001), decreased LV dp/dt max (CIH, 5072 Ϯ 2191; HC, 6596 Ϯ 720 mm Hg/second; p Ͻ 0.039), and decreased cardiac output (CIH, 48.2 Ϯ 10.5; HC, 64.1 Ϯ 10.9 ml/minute; p Ͻ 0.001). LV myocardial lipid peroxides were greater (CIH, 1,258 Ϯ 703; HC 715 Ϯ 240 m/mg protein; p Ͻ 0.05) and LV myocardial superoxide dismutase levels were lower (CIH, 10.3 Ϯ 4.9; HC, 18.6 Ϯ 8.2 U/mg protein; p Ͻ 0.05) with CIH. Conclusions: CIH leads to oxidative stress and LV myocardial dysfunction.
Effects of aging on the cardiac remodeling induced by chronic high-altitude hypoxia in rat
American Journal of Physiology-Heart and Circulatory Physiology, 2004
Effects of chronic high-altitude hypoxia on the remodeling of right ventricle were examined in three age groups of rats: 2, 6, and 18 mo. The extent of right ventricular (RV) hypertrophy (RVH) showed an age-associated diminution. RV cell size and pericellular fibrosis showed a significant increase in the 2- and 6-mo-old exposed rats but not in the 18-mo-old exposed rats compared with control. A hyperplasic response was underscored in the three exposed age groups but appeared less pronounced in the 18-mo-old rats. A significant decrease in the transient outward potassium current ( Ito) density was observed in RV cell only in the 2-mo-old exposed group compared with the control group. In the control group, there was a clear tendency for Ito density to decrease as a function of age. The sustained outward current density was modified neither by the hypoxia condition nor by the age. Neither the cytochrome c oxidase activity nor the heat shock protein 72 content in the RV was altered afte...
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.
Annals of the New York Academy of Sciences, 1999
The aim of the present study was to compare the capacity of the oxidative metabolism (total activity of cytochrome c oxidase, COX) in the right and left ventricular myocardium of adult rats exposed to intermittent high altitude (IHA) hypoxia simulated in a barochamber (5,000 m, 8 h/day, 5 days/wk, for a total of 32 exposures). In male and female rats, IHA induced significant increases of the right ventricular (RV) weight and protein content, whereas left ventricular (LV) weight and protein content remained unaffected. Consequently, the RV/LV ratio in both sexes markedly increased. Similarly, IHA induced an increase of the total activity of COX in RV in both sexes. The specific activities of COX in homogenate as well as in isolated mitochondria were not changed in IHA-exposed animals, which indicates that the increase of total activity of COX is proportional to the increase of total protein content and RV weight.
Regression of ventricular hypertrophy abolishes cardiocyte vulnerability to acute hypoxia
The Anatomical Record, 1990
Left ventricular hypertrophy (LVH) secondary to a pressure overload commonly leads to perfusion abnormalities that may limit oxygen delivery to the myocardium and, therefore, result in cardiocyte intracellular damage. We initiated this study to test the hypothesis that the increased vulnerability of the hypertrophied left ventricle to acute hypoxia is minimized when LVH regresses and maximal coronary flow returns to normal. Six-month-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were divided into control or one of two antihypertensive treatment groups. A 3-month treatment consisted of captopril (75-100 mg/kg) or hydralazine (80-160 mg/L) with hydrochlorothiazide (500 mg/L) added to each therapy. At the conclusion of the treatment period, the rats were administered a 7% O2-93% N2 gas mixture for 20 minutes to induce acute hypoxic stress during which time hemodynamics, blood gases, and pH were monitored. The heart was then rapidly fixed by vascular perfusion and prepared for electron microscopy. Captopril and hydralazine were equally effective in lowering arterial pressure in both strains, but only captopril was efficacious in reducing heart mass. Hypoxia-induced changes in hemodynamics, blood gases, and pH were similar in all of the groups; PO2 was decreased by about 70%. The electron micrographs revealed that the hypertrophied left ventricle consistently showed morphologic evidence of hypoxic damage (as indicated by T-tubular swelling, intracellular edema, and mitochondrial alterations); in contrast hypoxia had little effect on the non-hypertrophied ventricle. Captopril treatment resulted in a disappearance of the lability to hypoxic damage while hydralazine caused a small reduction in the frequency of hypoxic damage. In conclusion, reversal of hypertension alone had little effect on cardiocyte vulnerability to acute hypoxia, but reversal of hypertension in conjunction with regression of LVH prevented the intracellular damage characteristic of hypoxia. Thus, LVH and its associated maximal perfusion decrement, rather than hypertension per se, underlie cardiocyte vulnerability to hypoxic stress.
Effects of Normobaric Hypoxia and Adrenergic Blockade over 72 h on Cardiac Function in Rats
International Journal of Molecular Sciences
In rats, acute normobaric hypoxia depressed left ventricular (LV) inotropic function. After 24 h of hypoxic exposure, a slight recovery of LV function occurred. We speculated that prolonged hypoxia (72 h) would induce acclimatization and, hence, recovery of LV function. Moreover, we investigated biomarkers of nitrosative stress and apoptosis as possible causes of hypoxic LV depression. To elucidate the role of hypoxic sympathetic activation, we studied whether adrenergic blockade would further deteriorate the general state of the animals and their cardiac function. Ninety-four rats were exposed over 72 h either to normal room air (N) or to normobaric hypoxia (H). The rodents received infusion (0.1 mL/h) with 0.9% NaCl or with different adrenergic blockers. Despite clear signs of acclimatization to hypoxia, the LV depression continued persistently after 72 h of hypoxia. Immunohistochemical analyses revealed significant increases in markers of nitrosative stress, adenosine triphosphat...