Intermittent high altitude hypoxia protects the heart against lethal Ca2+ overload injury

Xie, Yan; Zhu, Wuqiang; Zhu, Yi; Chen, Le; Zhou, Zhao-Nian; Yang, Huang‐Tian

doi:10.1016/j.lfs.2004.09.017

Cited by 38 publications

(34 citation statements)

References 36 publications

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“…It has been shown that more ROS are generated in isolated mitochondria during reoxygenation after hypoxia than after anoxia, suggesting that the mitochondria-derived ROS rely to a certain extent on mitochondrial function (28). We (47,54) have reported previously that IHH effectively protects mitochondrial structure and function after myocardial I/R injury. Moreover, the abolishment of the IHH-induced increase in ROS production and cardioprotection by the mitochondrial K ATP channel inhibitor 5-HD (Figs.…”

Section: Mitochondria As the Main Source Of Ros In Ihh-induced Cardiomentioning

confidence: 80%

Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion

Wang

Chen

Zhang

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion. Am J Physiol Heart Circ Physiol 301: H1695-H1705, 2011. First published August 5, 2011; doi:10.1152/ajpheart.00276.2011.-Intermittent hypobaric hypoxia (IHH) protects hearts against ischemiareperfusion (I/R) injury, but the underlying mechanisms are far from clear. ROS are paradoxically regarded as a major cause of myocardial I/R injury and a trigger of cardioprotection. In the present study, we investigated whether the ROS generated during early reperfusion contribute to IHH-induced cardioprotection. Using isolated perfused rat hearts, we found that IHH significantly improved the postischemic recovery of left ventricular (LV) contractile function with a concurrent reduction of lactate dehydrogenase release and myocardial infarct size (20.5 Ϯ 5.3% in IHH vs. 42.1 Ϯ 3.8% in the normoxic control, P Ͻ 0.01) after I/R. Meanwhile, IHH enhanced the production of protein carbonyls and malondialdehyde, respective products of protein oxidation and lipid peroxidation, in the reperfused myocardium and ROS generation in reperfused cardiomyocytes. Such effects were blocked by the mitochondrial ATP-sensitive K ϩ channel inhibitor 5-hydroxydecanoate. Moreover, the IHH-improved postischemic LV performance, enhanced phosphorylation of PKB (Akt), PKC-ε, and glycogen synthase kinase-3␤, as well as translocation of PKC-ε were not affected by applying H 2O2 (20 mol/l) during early reperfusion but were abolished by the ROS scavengers N-(2-mercaptopropionyl-)glycine (MPG) and manganese (III) tetrakis (1-methyl-4-pyridyl)porphyrin. Furthermore, IHH-reduced lactate dehydrogenase release and infarct size were reversed by MPG. Consistently, inhibition of Akt with wortmannin and PKC-ε with εV1-2 abrogated the IHH-improved postischemic LV performance. These findings suggest that IHHinduced cardioprotection depends on elevated ROS production during early reperfusion.reactive oxygen species; ischemia-reperfusion injury EARLY REPERFUSION during evolving myocardial infarction is essential for saving the myocardium, but lethal reperfusion injury can occur and limit the beneficial effects (49). A number of cardioprotective strategies have been developed to ameliorate or retard the irreversible injury. However, the clinical translation of these strategies has failed to achieve the anticipated results (13, 34). Intermittent hypobaric hypoxia (IHH) has been shown to protect the heart against ischemia-reperfusion (I/R) injury by improving the manifestations including contractile dysfunction (3, 33), arrhythmias (31, 52), and cell death (8,27). Recently, we (48) revealed a therapeutic effect of IHH on permanent coronary artery ligation-induced myocardial infarction by attenuating infarct size, myocardial fibrosis, and apoptosis and improving cardiac performance. Because IHH is a relatively simple intervention with a longer protection duration and fewer adverse effects and may offer profound benefit to patients ...

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Section: Mitochondria As the Main Source Of Ros In Ihh-induced Cardiomentioning

confidence: 80%

Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion

Wang

Chen

Zhang

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…In addition to modulating Ca 2ϩ -handling pathways, the cardioprotective effects of IH have been independently attributed to mechanisms leading to opening of plasma and/or mitochondrial membrane K ATP channels (153,255,274,275). Adult and neonatal rats exhibited diminished frequency of ischemia-induced, K ATP channel-dependent arrhythmias, smaller infarct size and better postischemic contractility recovery following IH exposure (12,153,161).…”

Section: Circulatory Systemmentioning

confidence: 99%

Hypoxia. 4. Hypoxia and ion channel function

Shimoda

Polàk

2011

American Journal of Physiology-Cell Physiology

100

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The ability to sense and respond to oxygen deprivation is required for survival; thus, understanding the mechanisms by which changes in oxygen are linked to cell viability and function is of great importance. Ion channels play a critical role in regulating cell function in a wide variety of biological processes, including neuronal transmission, control of ventilation, cardiac contractility, and control of vasomotor tone. Since the 1988 discovery of oxygen-sensitive potassium channels in chemoreceptors, the effect of hypoxia on an assortment of ion channels has been studied in an array of cell types. In this review, we describe the effects of both acute and sustained hypoxia (continuous and intermittent) on mammalian ion channels in several tissues, the mode of action, and their contribution to diverse cellular processes. oxygen deprivation; mammalian ion channels; oxygen homeostasis SENSING and appropriately responding to changes in O 2 concentration is of paramount importance for the survival of all organisms. Over time, O 2 homeostasis has evolved into a complex system to regulate O 2 delivery and use. While the rapid response to acute reductions in O 2 concentration typically results from processes that alter preexisting proteins, such as phosphorylation, stabilization, dimerization, or degradation, durable adaptation to prolonged hypoxic insult requires a coordinated response at the level of gene transcription. Since a deficit in O 2 is an important component of various physiological processes and the pathogenesis of numerous diseases, understanding the mechanisms by which changes in O 2 are linked to cell function is of great interest.Ion channels play a critical role in regulating a wide variety of biological processes, including neuronal transmission; control of ventillation; contraction of cardiac, skeletal, and smooth muscle; transport of nutrients and ions across the epithelium; T-cell activation; and glucose metabolism and pancreatic ␤-cell insulin release. To date, over 300 types of ion channels, differing in their mode of activation (voltage-dependent or -independent, ligand-gated, mechanosensitive, pH) and their ionic permeability (K ϩ , Ca 2ϩ , Cl Ϫ , Na ϩ ), have been identified. This heterogeneity in ion channel populations provides an astonishing array of variable responses within and between cell types. In 1988, a report demonstrating that rabbit carotid body glomus cells express an O 2 -sensitive potassium channel ushered in a new era of research exploring whether ion channel activity could be regulated in response to changes in O 2 availability (131). Since that initial description of an O 2 -regulated ion channel, an abundance of work has been produced indicating that a variety of ion channels spread across the different ion channel families are O 2 sensitive and exhibit changes in channel activity with acute hypoxia and alterations in channel quantity with prolonged hypoxic challenge. Although a great amount of work has been devoted to the study of hypoxia and ion channels in reptiles, amp...

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“…Moderate chronic intermittent hypobaric hypoxia (CIHH), similar to ischemic preconditioning and long-term adaptation to high-altitude hypoxia, protects the heart against I/R injury [9,10,11,12]. This CIHH-induced cardiac protection persists longer than ischemic preconditioning [13,14] and is associated with less side effects on the body, such as polycythemia, right ventricular hypertrophy and pulmonary hypertension compared with long-term adaptation to high-altitude hypoxia [15,16,17]. In addition, CIHH increases the electrical stability of the cell membrane, preserves the contractility of the myocardium, and prevents apoptosis of cardiomyocytes [18,19,20,21].…”

Section: Introductionmentioning

confidence: 99%

Chronic Intermittent Hypobaric Hypoxia Ameliorates Ischemia/Reperfusion-Induced Calcium Overload in Heart via Na⁺/Ca²⁺Exchanger in Developing Rats

Hui

et al. 2014

Cell Physiol Biochem

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Background/Aims: Chronic intermittent hypobaric hypoxia (CIHH) protects the heart against ischemia/reperfusion (I/R) injury. This study investigated the calcium homeostasis mechanism and the role of Na⁺/Ca²⁺ exchanger (NCX) in the cardiac protective effect of CIHH in developing rats. Methods: Neonatal male rats received CIHH treatment or no treatment (control) in a hypobaric chamber simulating 3000-meter altitude for 42 days. The left ventricular function of isolated hearts was evaluated after 30 minutes of ischemia and 60 minutes of reperfusion. Myocardial infarct size, intracellular Ca²⁺ concentration ([Ca²⁺]_i), Na⁺-Ca²⁺ exchanger currents (I_Na/Ca) in ventricular myocytes, and NCX1 protein level in the sarcolemmal membrane were determined. Results: The recovery of cardiac function after I/R was improved, with the myocardial infarct size reduced, in CIHH rats compared with control rats (p<0.05). These effects were attenuated by Bay K8644, an L-type Ca²⁺ channel agonist, or ryanodine, a sarcoplasmic reticulum Ca²⁺ channel receptor activator. Furthermore, the increases in [Ca²⁺]_i during I/R were blunted in CIHH rats, but this effect was abolished by Bay K8644 or chelerythrine, a protein kinase C (PKC) inhibitor. The I_Na/Ca was decreased and the reversal potential of I_Na/Ca was shifted toward negative potential during simulated ischemia in the control cardiomyocytes (p<0.05). The inhibition of NCX1 protein expression during I/R was smaller in the CIHH rats than in the control rats (p<0.05). Conclusion: These data suggest that CIHH protects developing rat hearts during I/R by enhancing the resistance against calcium overload and by preserving normal I_Na/Ca and NCX1 protein. PKC activation might be involved in this protective process of CIHH.

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Intermittent high altitude hypoxia protects the heart against lethal Ca2+ overload injury

Cited by 38 publications

References 36 publications

Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion

Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion

Hypoxia. 4. Hypoxia and ion channel function

Chronic Intermittent Hypobaric Hypoxia Ameliorates Ischemia/Reperfusion-Induced Calcium Overload in Heart via Na⁺/Ca²⁺Exchanger in Developing Rats

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Intermittent high altitude hypoxia protects the heart against lethal Ca2+ overload injury

Cited by 38 publications

References 36 publications

Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion

Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion

Hypoxia. 4. Hypoxia and ion channel function

Chronic Intermittent Hypobaric Hypoxia Ameliorates Ischemia/Reperfusion-Induced Calcium Overload in Heart via Na+/Ca2+Exchanger in Developing Rats

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Chronic Intermittent Hypobaric Hypoxia Ameliorates Ischemia/Reperfusion-Induced Calcium Overload in Heart via Na⁺/Ca²⁺Exchanger in Developing Rats