Abstract: Despite its well-known role in red blood cell production, it is now accepted that erythropoietin (Epo) has other physiological functions. Epo and its receptors are expressed in many tissues, such as the brain and heart. The presence of Epo/Epo receptors in these organs suggests other roles than those usually assigned to this protein. Thus, the aim of this review is to describe the effects of Epo deficiency on adaptation to normoxic and hypoxic environments and to suggest a key role of Epo on main physiological adaptive functions. Our original model of Epo-deficient (Epo-TAg h ) mice allowed us to improve our knowledge of the possible role of Epo in O 2 homeostasis. The use of anemic transgenic mice revealed Epo as a crucial component of adaptation to hypoxia. Epo-TAg h mice survive well in hypoxic conditions despite low hematocrit. Furthermore, Epo plays a key role in neural control of ventilatory acclimatization and response to hypoxia, in deformability of red blood cells, in cerebral and cardiac angiogenesis, and in neuro- and cardioprotection. Keywords: Epo-TAg h mice, mouse model, physiological functions, hypoxia
Chronic anemia-induced hypoxia triggers regulatory pathways that mediate long-term adaptive cardiac and cerebral changes, particularly at the transcriptional level. These adaptative mechanisms include a regulated cerebral blood flow and cardiac output, angiogenesis and cytoprotection triggered by hypoxia-inducible factor 1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), neuronal nitric oxide synthase (nNOS) and Epo pathways. All these compensatory mechanisms aim to optimize oxygen delivery and to protect the brain and heart from hypoxic injury. We reviewed the effects of chronic hypobaric hypoxia as well as chronic anemia in the heart and brain, and we compared for the first time the effects of chronic hypobaric hypoxia combined with a severe lack of Epo (chronic anemia) in these vital organs. Functional cardiac adaptations such as cardiac hypertrophy, increased cardiac output as well as angiogenesis occurred along with the activation of HIF1α/VEGF and Epo/EpoR pathways under chronic anemia or hypoxia. Similarly, cerebrovascular adaptations take place through the same molecular mechanisms under chronic hypoxia or anemia. However, when both arterial pressure and content of oxygen are decreased, the cerebral and cardiac adaptative mechanisms showed their limitations. In addition, cerebral and cardiac cell injuries may have occurred following the combined effect of chronic anemia and hypoxia. By emphasizing the anemia and hypoxia-induced cerebral and myocardial adaptations, this review highlighted the crucial role of Epo in its non-erythropoietic functions such as angiogenesis and neuroprotection. Indeed, a better understanding of these protective mechanisms is of great clinical importance to the development of new therapeutic strategies for the management of ischemic heart and brain.
In this study, our objective was to explore the knowledge of Irritable Bowel syndrome (IBS) among university female students in the Kingdom of Saudi Arabia (KSA). A cross-sectional study was conducted where 307 university students were surveyed using a self-administered questionnaire to assess their awareness. The questionnaire was based on the socio-demographic and life-style characteristics of the students to evaluate the prevalence of IBS in the community. About 60% of the population in the age group of 18-20 years are at a high risk of suffering from IBS. However, no significant difference is demonstrated between lifestyle habits such as consumption of fast and spicy foods and physical activities and onset of IBS among the students. Nevertheless, frequent episodes of exercise in a week may reduce the probability of IBS onset. Interestingly, almost half of the student population mentioned that they were taking antibiotics and their sleep was interrupted as they woke up in the middle of the night. Also, majority of the population indicated that their stool texture was different, either hard or loose associated with a pain and distended abdomen followed with gastritis. Abdominal discomfort, feeling of bloating, altered texture of stool and urgency to defecate could be due to the development of psychological stress associated with academics, which possibly intensifies the disease symptoms. Initial findings from our study justifies the need of future longitudinal surveys to validate the existence of psychological stressors and other risk factors in the development of IBS subtypes.
This study was performed to estimate the knowledge and awareness of the university students about the presence of ventricular septal defects (VSDs) in Saudi Arabia. A cross-sectional study was performed in Princess Nourah bint Abdulrahman University (PNU) campus where a total of 350 female students in the age group of 17-25 years were surveyed using a clinically appropriate structurally designed questionnaire. Only a third of the population were familiar with the definition and anatomical location of VSDs. Although, majority of the population believed that VSDs are subject to cure, a negligible population of the students were aware that VSDs are associated with pulmonary hypertension in adults, although, about half of the population were associated with people who were suffering from VSDs. Even though promising, only half of the population were aware of rapid breathing in infants and association of endocarditis with VSDs. Regarding life-style factors, only 18% of the population knew that VSD patients are restrained from different physical activities. This population study is the first of its kind to determine the knowledge of the university students regarding the characteristics, symptoms, risk-factors, management and life-style factors associated with VSD. It identified the imperative need to organize campaigns to raise awareness about the disease process and management among female population who will be future mothers since Awareness about VSDs can help manage the physical, social, cognitive and emotional well-being of the patients with better outcomes to reduce the mortality rate.
The objective of our study was to assess the role of neuronal nitric oxide synthase (nNOS) in the ventilatory acclimatization to hypoxia. We measured the ventilation in acclimatized Bl6/CBA mice breathing 21% and 8% oxygen, used a nNOS inhibitor, and assessed the expression of N-methyl-d-aspartate (NMDA) glutamate receptor and nNOS (mRNA and protein). Two groups of Bl6/CBA mice (n = 60) were exposed during 2 wk either to hypoxia [barometric pressure (PB) = 420 mmHg] or normoxia (PB = 760 mmHg). At the end of exposure the medulla was removed to measure the concentration of nitric oxide (NO) metabolites, the expression of NMDA-NR1 receptor, and nNOS by real-time RT-PCR and Western blot. We also measured the ventilatory response [fraction of inspired O(2) (Fi(O(2))) = 0.21 and 0.08] before and after S-methyl-l-thiocitrulline treatment (SMTC, nNOS inhibitor, 10 mg/kg ip). Chronic hypoxia caused an increase in ventilation that was reduced after SMTC treatment mainly through a decrease in tidal volume (Vt) in normoxia and in acute hypoxia. However, the difference observed in the magnitude of acute hypoxic ventilatory response [minute ventilation (Ve) 8% - Ve 21%] in acclimatized mice was not different. Acclimatization to hypoxia induced a rise in NMDA receptor as well as in nNOS and NO production. In conclusion, our study provides evidence that activation of nNOS is involved in the ventilatory acclimatization to hypoxia in mice but not in the hypoxic ventilatory response (HVR) while the increased expression of NMDA receptor expression in the medulla of chronically hypoxic mice plays a role in acute HVR. These results are therefore consistent with central nervous system plasticity, partially involved in ventilatory acclimatization to hypoxia through nNOS.
The N-Methyl-d-Aspartate (NMDA) receptors - neuronal nitric oxide synthase (nNOS) pathway is involved in the ventilatory response to hypoxia. The objective was to assess the possible effect of erythropoietin deficiency and chronic exposure to hypoxia on this pathway during ventilatory response to acute hypoxia. Wild-type (WT) and erythropoietin-deficient (Epo-TAg(h)) male mice were exposed (14 days) either to hypobaric hypoxia (Pb = 435 mmHg) or to normoxia. The ventilation was measured at 21% or 8% O2 after injection of vehicle (NaCl), nNOS inhibitor (SMTC) or NMDA receptor antagonist (MK-801). Nitric oxide production and the expression of NMDA receptor and nNOS were assessed by real-time RT-PCR and Western blot analyses in the medulla. At rest, Epo-TAg(h) mice displayed normal ventilatory parameters at 21% O2 but did not respond to acute hypoxia despite a larger expression of NMDA receptors and nNOS in the medulla. Ventilatory acclimatization to hypoxia was observed in WT but was absent in Epo-TAg(h) mice. nNOS inhibition blunted the hypoxic ventilatory acclimatization of WT mice without any effect in Epo-TAg(h) mice. Acute hypoxic ventilatory response (HVR) was increased after chronic hypoxia in WT but remained unchanged in Epo-TAg(h) mice. Ventilatory response to acute hypoxia was modified by MK-801 injection in WT and Epo-TAg(h) mice. The results confirm that adequate erythropoietin level is necessary to obtain an appropriate HVR and a significant ventilatory acclimatization to hypoxia. Furthermore, erythropoietin plays a potential catalyzing role in the NMDA-NO central pathway during the ventilatory response and acclimatization to hypoxia.
Anemia and hypoxia in rats result in an increase in factors potentially involved in cerebral angiogenesis. Therefore, the aim of this study was to assess the effect of chronic anemia and/or chronic hypoxia on cerebral cellular responses and angiogenesis in wild-type and anemic transgenic mice. These studies were done in erythropoietin-deficient mice (Epo-TAg(h)) in normoxia and following acute (one day) and chronic (14 days, barometric pressure = 420 mmHg) hypoxia. In normoxia, Epo-TAg(h) mice showed an increase in transcript and protein levels of hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), erythropoietin receptors (EpoR), phospho-STAT-5/STAT-5 ratio, and neuronal neuronal nitric oxide synthase (nNOS) along with a higher cerebral capillary density. In wild-type (WT) mice, acute hypoxia increased all of the studied factors, while in chronic hypoxia, HIF-1alpha, EpoR, phospho-STAT-5/STAT-5 ratio, nNOS, and inducible NOS remained elevated, with an increase in capillary density. Surprisingly, in Epo-TAg(h) mice, chronic hypoxia did not further increase any factor except the nitric oxide metabolites, while HIF-1alpha, EpoR, and phospho-STAT-5/STAT-5 ratio were reduced. Normoxic Epo-TAg(h) mice developed cerebral angiogenesis through the HIF-1alpha/VEGF pathway. In acute hypoxia, WT mice up-regulated all of the studied factors, including cerebral NO. Polycythemia and angiogenesis occurred with acclimatization to chronic hypoxia only in WT mice. In Epo-TAg(h), the decrease in HIF-1alpha, VEGF proteins, and phospho-STAT-5 ratio in chronic hypoxia suggest that neuroprotective and angiogenesis pathways are altered.
