Expression of Key Enzymes in Glucose Metabolism in Chronic Mountain Sickness and Its Correlation with Phenotype / 中国实验血液学杂志

OBJECTIVE@#To explore the pathogenesis of erythrocytosis by detecting the key enzymes of glucose metabolism and glucose transporter in bone marrow erythrocytes of chronic mountain sickness (CMS), and analyzing its correlation with hemoglobin.@*METHODS@#Twenty CMS patients hospitalized in Qinghai Provincial People's Hospital from January 2019 to December 2020 were selected as CMS group. Twenty males with leukocyte count > 3.5×109/L who had accepted bone marrow aspiration and had normal result were taken as control group. The mRNA and protein expression of key enzymes and glucose transporter in glucose metabolism in bone marrow CD71+ erythrocytes were detected by real time qPCR and Western blot, respectively. Glucose, lactic acid and 2,3-diphosphoglycerate in the bone marrow supernatant and serum were tested by ELISA. The mRNA and protein expression of key enzymes and glucose transporter, glucose, lactic acid and 2,3-diphosphoglycerate of the two groups were compared. Pearson correlation was used to analyze the correlation between key enzymes, glucose transporter in glucose metabolism in bone marrow CD71+ erythrocytes and hemoglobin.@*RESULTS@#The expression of HK2, GLUT1 and GLUT2 mRNA in the CMS group were higher than those in the control group (P<0.001), while the expression of HK1, OGDH and COX5B mRNA were not different. The expression of HK2, GLUT1 and GLUT2 protein in the CMS group were higher than those in the control group (P<0.05). The levels of glucose and lactic acid in the bone marrow supernatant and serum in the CMS group were not different from those in the control group, while the level of 2,3-diphosphoglycerate was higher (P<0.001). Both HK2 and GLUT2 proteins were positively correlated with hemoglobin (r=0.511, 0.717).@*CONCLUSION@#CMS patients may increase glycolysis by increasing the expression of HK2, and promote the utilization of glucose through high expression of GLUT1 and GLUT2 to meet the need of energy supply.

Un ejemplo de respuesta adaptativa integrada: la aclimatación humana a la altitud / An example of integrated adaptive response: human acclimatization to altitude

Se describen las respuestas fisiológicas que el ser humano desarrolla en respuesta a la exposición a la altitud geográfica. Se describen no sólo las alteraciones debidas a una mala coordinación de los ajustes fisiológicos desencadenados durante la aclimatación a la altura sino también sus manifestaciones clínicas más relevantes. Se detallan los mecanismos moleculares subyacentes a tales respuestas y cómo su mejor conocimiento puede permitir aplicar la exposición intermitente a hipoxia como una herramienta útil para la resolución o alivio de determinadas alteraciones y patologías.

We depict the physiological responses developed by the human body in response to the exposure to geographic altitude. The main alterations due to a noncoordinated setup of the physiological adjustments triggered during the acclimatization at altitude are also described, as its most relevant clinical manifestations. The molecular mechanisms underlying such responses are detailed, and how a better knowledge of these processes can allow us to apply intermittent exposure to hypoxia programs as a useful tool for the resolution or relief of certain disorders and pathologies.

Función ventricular derecha en residentes nativos a gran altura / Right ventricular function in native residents at high altitude

Los adaptados genéticamente a la altura son los tibetanos, sherpas y etíopes; los aymaras y quechuas están aclimatados (Bolivia, Perú y norte de Chile). En Bolivia el mal crónico de montaña afecta 10% de la población masculina. El objetivo fue determinar la función ventricular derecha en residentes sanos y con mal crónico de montaña mediante ecocardiografía transtoráxica. Se utilizaron participantes sanos y con mal crónico de montaña admitidos por el IBBA, desde el año 2012 al 2013. Las variables tomadas son: demográficas, espirometria forzada, gasometría arterial en reposo e hiperoxia, ECG y ECCTT. Los controles (n 40), la edad promedio (44,13±9,69 años), predominio masculino y sobrepeso (IMC 26,27±6,68kg /m2), procedentes de La Paz 3.600 msnm (54%), Potosí 4.000 msnm (22%), El Alto 4.100 msnm (15%) y Oruro 3.800 msnm (9%), el promedio de Hematocrito 51,34±2,91%, hemoglobina 17,15±0,89gr/ dl, Espirometria forzada y Gasometría arterial en reposo e hiperoxia normales, la ECCTT muestra hipertensión pulmonar leve (35,85±3,64mmHg), aumento de grosor del VD (0,51±0,08), TAPSE (2,94±3,85mmHg) y el índice de Tei (0,44±0,22) normales. Los casos (n 40), la edad promedio (48,43±8,08 años), predominio masculino y sobrepeso (IMC 29,54±3,41kg / m2), procedente de La Paz 3.600 msnm (56%), Potosí 4.000 msnm (24%), El Alto 4.100 msnm (13%) y Oruro 3.800 msnm (7%), Hematocrito 63,08±6,2%, Hemoglobina 21,01±2,01gr/dl con eritrotrocitosis, espirometría forzada normal, gasometría arterial en reposo con hipoxemia moderada (PaO2 51,73±4,68mmHg), hipocapnia (PaCO2 27,62±2,04mmHg) y gradiente Alveolo-arterial aumentado (7,61±3,15). Gasometría arterial en hiperoxia descarta shunt (PaO2 308,9±52,58mmHg), el ECG muestra 2 de 11 criterios de crecimiento VD, la ECCTT con hipertensión pulmonar moderada (PSAP 45,22±5,69mmHg), aumento de grosor del VD (0,73±0,22), TAPSE (2,08±0,18cm), normal e índice de Tei (0,51±0,10) ligeramente aumentado. Se concluyó que la función ventricular derecha se encuentra conservada, a pesar de tener hipertensión pulmonar leve (controles) y moderada (casos), con aumento del grosor del ventrículo derecho.

Those genetically adapted to the height are the Tibetans, Sherpas, and Ethiopians; the Aymara and Quechuas are acclimatized (Bolivia, Peru, and northern Chile). In Bolivia, chronic mountain sickness affects 10% of the male population. The objective was to determine the right ventricular function in healthy residents with chronic mountain sickness using transthoracic echocardiography. Use the healthy and chronically ill mountain participants admitted by the IBBA, from 2012 to 2013. The variables taken are demographic, forced spirometry, arterial blood gas at rest and hyperoxia, ECG, and ECCTT. Controls (n 40), average age (44.13 ± 9.69 years), male predominance and overweight (BMI 26.27 ± 6.68kg / m2), frequency from La Paz 3,600 masl (54%), Potosí 4,000 masl (22%), El Alto 4,100 masl (15%) and Oruro 3,800 masl (9%), the average Hematocrit 51.34 ± 2.91%, hemoglobin 17.15 ± 0.89gr / dl, Forced spirometry y Resting arterial blood gas and normal hyperoxia, ECCTT shows mild pulmonary hypertension (35.85 ± 3.64 mmHg), increased RV thickness (0.51 ± 0.08), TAPSE (2.94 ± 3.85 mmHg ) and the Tei index (0.44 ± 0.22) normal. The cases (n 40), the average age (48.43 ± 8.08 years), male predominance and overweight (BMI 29.54 ± 3.41kg / m2), derived from La Paz 3,600 masl (56%), Potosí 4,000 masl (24%), El Alto 4,100 masl (13%) and Oruro 3,800 masl (7%), Hematocrit 63.08 ± 6.2%, Hemoglobin 21.01 ± 2.01gr / dl with erythrocytosis, normal forced spirometry , resting arterial blood gas with moderate hypoxemia (PaO2 51.73 ± 4.68mmHg), hypocapnia (PaCO2 27.62 ± 2.04mmHg) and increased Alveolo-arterial gradient (7.61 ± 3.15). Arterial blood gas in hyperoxia rules out shunt (PaO2 308.9 ± 52.58mmHg), ECG shows 2 of 11 RV growth criteria, ECCTT with moderate pulmonary hypertension (PSAP 45.22 ± 5.69mmHg), increased RV thickness (0.73 ± 0.22), TAPSE (2.08 ± 0.18cm), normal and Tei index (0.51 ± 0.10) slightly increased. It was concluded that the right ventricular function is preserved, a weight of having mild pulmonary hypertension (controls) and moderate (cases), with increased thickness of the right ventricle.

Prevalence and risk factors of chronic mountain sickness in Pamirs plateau / 中国应用生理学杂志

OBJECTIVE@#To investigate the prevalence of chronic mountain sickness (CMS) and its predisposing factors in Pamirs plateau and analysis clinical feature and risk factors.@*METHODS@#Eight hundred and twenty-four individuals in Pamirs plateau were surveyed used Qinghai CMS scoring system. Demographics, BP, SaO, heart rate and specified symptoms of CMS were recorded, Hb level was estimated.@*RESULTS@#Overall CMS prevalence was 22.08%, including 21.84% mild and 0.24% moderate without severe patient. Gender, nation, age, immigration time, altitude, occupation and accommodation mode were risk factors for CMS (<0.05 or <0.01), CMS prevalence was higher than HAPC rate both in male and female (χ=90.59 and 44.13, <0.01). Multiple linear regression analysis showed age, BMI, SaO and systolic pressure correlated with CMS (<0.01).@*CONCLUSIONS@#Chronic mountain sickness prevalence in Pamirs plateau is rather high but high altitude polycythemia prevalence is low, so the disease type is high altitude deterioration. Work and exercise more reasonable to avoid overtiredness, oxygen inhalation to raise blood oxygen saturation, control blood pressure and resting therapy can improve CMS symptom and decrease prevalence.

Analysis of hospitalized cases with atrial fibrillation in high altitude areas in Tibet / 中国介入心脏病学杂志

Objective To analyze the etiological or associated factors and the treatment of patients with atrial fi brillation in high altitude areas in Tibet. Methods The clinical data of atrial fi brillation patients hospitalized in our hospital during January 2012 to Jane 2016 were analyzed retrospectively. Results (1) A total of 442 patients (male:female,1.2:1) were included in the study with ages of 30-96(65.9±12.3) years. The percentages of paroxysmal, persistent and permanent atrial fi brillation were 14.9%, 69.2%, and 15.8% respectively. The associated factors of atrial fi brillation included hypertension (53.4%), rheumatic heart disease (7.5%),chronic mountain sickness (10.6%), coronary heart disease(5.7%), hyperthyroidism (6.1%) and diabetes (9.0%).(2)Only 42 patients (9.5%) had evaluation with CHADS2score during hospitalization and actually 74.6% patients scored≥2. Twenty-one patients were restored to sinus rhythm during hospitalization and no patients had radiofrequency ablation.Conclusions The associated factors of atrial fi brillation in high altitude areas are similar to other areas. Thrombosis risk evaluation and anticoagulation therapy was not sufficient. Rhythm control rate was low and development of radio frequency ablation therapy should be considered.

The value of diffusion kurtosis imaging combined with diffusion weighted imaging in evaluating the microstructure of cerebral gray and white matter in chronic mountain sickness / 实用放射学杂志

Objective To explore the gray and white matter microstructures in the brain of patients with different degrees of chronic mountain sickness(CMS).Methods 30 cases of CMS (10 cases in each group divided into mild,moderate and severe groups according to the severity)were collected as experimental group,and 10 normal adults in high altitude area were collected as the normal control group.All cases underwent MRI conventional head sequences,diffusion weighted imaging (DWI)and diffusion kurtosis imaging (DKI)sequences.The values of mean kurtosis(MK),radial kurtosis(RK),kurtosis anisotropy(KA)and apparent diffusion coefficient(ADC) graphs were reconstructed by post-processing software respectively.Selected the region of interest(ROI)symmetrically and fixedly, then measured and analyzed the parameter values of ROI in the same area.Results Compared the CMS groups with normal control group,the diffusion parameters and ADC values in certain parts of deep gray matter nucleus and white matter fibers were statistically significant,and the difference was significant with the progression of the disease.Conclusion DKI combined with DWI has certain value in evaluating the gray and white matter microstructure of human brain,there are some difference in the brain microstructure between CMS patients and high altitude normal subjects,additionally,the difference in different degrees of CMS is diverse.

Diffusion kurtosis imaging for demonstrating the microstructure of brain gray and white matter in patients withchronic mountain sickness / 实用医学杂志

Objective To explore the differences between patients withchronic mountain sickness (CMS) and healthy people in the microstructure of brain gray and white matter by using diffusion kurtosis imaging (DKI). Methods 21 CMS patients were recruited to a study group and 20 healthy volunteers were assigned to a control group. Both groups received conventional MRI and DKI sequence scans. The mean kurtosis (MK) values ,radial kurtosis (RK) values and kurtosis anisotropy (KA) values in each region of interest (ROI) in the cerebral gray and white matter were measured and the same part of the left and right side ROI parameters was counted. The data satisfied the normal distribution and the paired samples t?test was used;the ROI parameters between the two groups in the same parts of the same side followed the normal distribution and the two independent samples t?test was used. Results The KA values in both sides of the anterior limb of internal capsule ,the MK values and RK values in bilateral caudate nucleus head and thalamus had side difference in CMS group. In both sides of the anterior limb of the internal capsule′s MK values,KA values and thalamus′s MK values,RK values existed side difference in the control group. The KA values of the right anterior limb in internal capsule were lower than those in the left in both groups;the right thalamus′s MK values and RK values were higher than the other side. The RK value in genu of corpus callosum differed significantly ,and it was lower the CMS group than in the control group. The difference of the KA values in corpus callosum ,the MK value in the left anterior limb of internal capsule ,the RK values in the left posterior limb of internal capsule ,the MK values in the right caudate nucleus head ,the MK values in bilateral lenticular nucleus and the MK values and KA values in the right thalamus were significant ,and they were higher inthe CMS group than in the control group. Conclusions The left and right cerebral hemispheric micro?structure is not exactly symmetrical between patients with CMS and healthy people living in high altitude areas , there are differences in some brain areas. The sensitivity and reactivity of brain tissue to high altitude hypoxia are different in patients with CMS ,there are various degrees of difference between the CMS and the normal in the corpus callosum,basal ganglia region and thalamus.

Preliminary study of patients with chronic mountain sickness by GC-TOF-MS based serum metabolomics analysis / 中国病理生理杂志

AIM:To evaluate specific metabolomics profiles in the serum of patients with chronic mountain sickness (CMS) and to explore the potential metabolic biomarkers in the native Tibetans living on the Qinghai-Tibet Plateau.METHODS:A gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) approach as a metabolomics technique was used to evaluate metabolic differences.The native Tibetan CMS patients (n =10) and healthy Tibetan controls (n =10) were enrolled from YuShu in Qinghai province in this study.The serum samples were collected and analyzed by GC-TOF-MS coupled with a series of multivariate statistical analyses such as principal component analysis (PCA),partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA).RESULTS:The intergroup differences between CMS patients and control subjects have been observed.A list of differential metabolites and several top altered rnetabolic pathways have been identified.The levels of fumaric acid,an intermediate in the tricarboxylic acid (TCA) cycle,and inosine were highly upregulated in the CMS patients,suggesting a greater effort to hypoxic adaptation in high elevation area.Other differential metabolites,such as methyl phosphate,2-ketoadipate,lyxose and phytanic acid were also identified.Importantly,the differential metabolites possessed higher area under the ROC curve (AUC) values,indicating an excellent clinical ability for the prediction of CMS.Increased levels of amino acids (isoleucine,glycine,serine,L-cysteine,citrulline and trimethyllysine) were detected in CMS group,yet significantly decreased levels of sulfuric acid,oxamic acid,lyxose and glutamine were also detected in CMS group than those in control group.At the same time,the levels of ribose and glucose-1-phosphate were markedly elevated in CMS group (P ＜ 0.05).CONCLUSION:The metabolic activities are significantly altered in the serum of CMS patients.High altitude hypoxia may act on the disturbed glucose metabolism and amino acid metabolism in part of the Tibetan triggered by CMS.

Preliminary study of patients with chronic mountain sickness by GC-TOF-MS based serum metabolomics analysis / 中国病理生理杂志

AIM:To evaluate specific metabolomics profiles in the serum of patients with chronic mountain sickness (CMS) and to explore the potential metabolic biomarkers in the native Tibetans living on the Qinghai-Tibet Plateau.METHODS:A gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) approach as a metabolomics technique was used to evaluate metabolic differences.The native Tibetan CMS patients (n =10) and healthy Tibetan controls (n =10) were enrolled from YuShu in Qinghai province in this study.The serum samples were collected and analyzed by GC-TOF-MS coupled with a series of multivariate statistical analyses such as principal component analysis (PCA),partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA).RESULTS:The intergroup differences between CMS patients and control subjects have been observed.A list of differential metabolites and several top altered rnetabolic pathways have been identified.The levels of fumaric acid,an intermediate in the tricarboxylic acid (TCA) cycle,and inosine were highly upregulated in the CMS patients,suggesting a greater effort to hypoxic adaptation in high elevation area.Other differential metabolites,such as methyl phosphate,2-ketoadipate,lyxose and phytanic acid were also identified.Importantly,the differential metabolites possessed higher area under the ROC curve (AUC) values,indicating an excellent clinical ability for the prediction of CMS.Increased levels of amino acids (isoleucine,glycine,serine,L-cysteine,citrulline and trimethyllysine) were detected in CMS group,yet significantly decreased levels of sulfuric acid,oxamic acid,lyxose and glutamine were also detected in CMS group than those in control group.At the same time,the levels of ribose and glucose-1-phosphate were markedly elevated in CMS group (P ＜ 0.05).CONCLUSION:The metabolic activities are significantly altered in the serum of CMS patients.High altitude hypoxia may act on the disturbed glucose metabolism and amino acid metabolism in part of the Tibetan triggered by CMS.

Chronic mountain sickness modulated cerebrovascular reactivity and biological effects on the related vascu-lar responses cytokines / 中国神经精神疾病杂志

Objective To investigate the influence of the chronic mountain sickness (chronic mountain sickness, CMS) on Cerebrovascular reactivity (CVR) and regulators of cerebrovascular responses. Methods Twenty-six CMS pa?tients and 23 healthy control group using transcranial Doppler ultrasound (Transcranial Doppler Ultrasoiund, TCD) as?sessment of CVR, enzyme-linked immunosorbent assay were applied to measure the serum levels of the endothelin (endo?thelin 1 , ET-1) and its receptor (endothelin receptor B, ETBR), endothelial nitric oxide synthase (endothelial nitric oxide synthase, eNOS) in CMS patients and healthy control. Results CVR (3.84 ± 3.01) was significantly lower in CMS patients than in the healthy control CVR (6.39 ± 6.87) (P <0.05); the serum concentration of ETBR in CMS patients was higher than in control [(386.07±281.57)μg/μL vs.(312.30±238.07)μg/μL] (P<0.05). Conclusions The cerebral circulation re?serve in CMS patients is significantly lower compared with healthy people. The regulation of vascular capacity by serum ET-1 and eNOS is similar between CMS patients and healthy control. The hypoxic vasodilatation in CMS patients is close?ly associated with cerebrovascular high expression of ETBR. This study may provide a scientific basis for the prevention and treatment of cerebral infarction in the patients with chronic mountain sicknes.

Expression of GDF-15 in chronic mountain sickness rat model and discussion of the relationship with GDF-15 and hepcidin / 实用医学杂志

Objective To determine the growth differential factor 15 (GDF-15) in CMS rat model, investigate the significance of GDF-15 in CMS and the relationship between GDF-15 and hepcidin. Methods 32 rats of CMS model were taken as experimental group (EXP), the other 16 rats fed in Xining (CON) were taken as control group. The mRNA and protein expression levels of GDF-15 were detected respectively. Results Compared with that in CON group, the level of mRNA and protein of GDF-15 were significantly higher in EXP group (P<0.01). GDF-15 and EPO had correlation in EXP (r=0.397, P=0.031), but had no correlation with serum hepcidin in EXP (r = -0.224, P = 0.218). Conclusion GDF-15 can promote CMS and represent erythrocytosis, while GDF-15 has no inhibition to the expression of hepcidin.

Eritrocitosis patológica de altura: caracterización biológica, diagnóstico y tratamiento / High alitude patthological erythrocytosis: biological characterization, diagnosis and treatmnnt

Introducción. Los pobladores de grandes alturas se adaptaron de modo diferentes, siguiendo rutas distintas con el mismo objetivo de suministro de oxígeno y la supervivencia. En el presente trabajo se caracteriza la Eritrocitosis Patológica de Altura y se demuestra la eficacia de la atorvastatina en el tratamiento. Material y métodos. Se estudiaron: Sujetos varones como Controles Normales (CN), y pacientes con Eritrocitosis Patológica de Altura (EPA), Eritrocitosis Secundaria (ES) y Policitemia Vera (PV). Se realizaron estudios de laboratorio y de biología molecular. Se realizó estudio clínico de fase 2 con atorvastatina. Resultados. La EPA presenta: eritropoyetina normal, apoptosis retardada de progenitores eritroides, crecimiento autónomo de BFU-E e hipersensibilidad a la eritropoyetina. La atorvastatina como tratamiento en pacientes con EPA disminuye la concentración de hemoglobina y remite la sintomatología de la hiperviscosidad sanguínea. Conclusiones. La EPA tiene características propias que la distinguen de otras eritrocitosis patológicas y la atorvastatina se constituye en tratamiento eficaz.

Introduction. The residents of high altitude get use to it in different ways, following the same purpose in order to supply oxygen and survival. In the present paper, we characterize the High Altitude Pathological Erythrocytosis disease and demonstrate the effectiveness of atorvastatin in its treatment. Material and methods. We studied male subjects as normal controls (CN), and patients with High Altitude Pathological Erythrocytosis (EPA), Secondary Erythrocytosis (ES) and Polycythemia Vera (PV). Laboratory and molecular biology studies were conducted. We developed in the study of 2nd phase with atorvastatin. Results. The EPA presents: normal erythropoietin, delayed erythroid progenitors apoptosis, autonomous growth of BFU-E and hypersensitivity to erythropoietin. The atorvastatin in patient with EPA, decreased hemoglobin concentration and eliminates the symptomatology of blood hyperviscosity Conclusions. The EPA has characteristics that distinguish it from other pathologic erythrocytosis and atorvastatin becomes an effective treatment.

Mecanismo molecllar de las estatinas en el tratamiento de la eritrocitosis patoológica de altura / Molecular mechanism of statins in the treatment of high altitude pathological erythroyytosis

Introducción La Eritrocitosis Patológica de Altura es la manifestación hematológica de la Enfermedad Crónica de Altura, por adaptación inadecuada a grandes alturas de genes reguladores de la eritropoyesis. Las estatinas son inhibidores de la vía del mevalonato involucrado en la regulación de la eritropoyesis. El presente trabajo describe los mecanismos moleculares de la inhibición de la eritropoyesis en pacientes con eritrocitosis patológicas. Material y métodos Se estudiaron 35 pacientes con eritrocitosis patológicas con radicatorias en las ciudades de La Paz y El Alto (3600 y 4000 msnm respectivamente). Se realizaron Cultivo de células progenitoras hematopoyéticas y Western Blot. Resultados Statins induce apoptosis of erythroid progenitors in the cell culture medium. Without the supplement of simvastatin the apoptosis was 12.3% and With simvastatin the apoptosis was 38.4% (p = 0.001). Furthermore statins inhibit the proliferation and differentiation of erythroid progenitors. Conclusiones Los mecanismos moleculares involucrados en la inhibición de la eritropoyesis son: a) Bloqueo de la isoprenilación de Rho y Ras, b) Inhibición de la fosforilación de Jak-2 y Stat-5, c) inhibición de la glicosilación del EpoR, d) Disminución de colesterol en microdominios de la membrana celular (raft lipid), e) Inducción de apoptosis a través de BCLxL y caspasa 9.

Introduction The High altitude Pathological Erythrocytosis is the chronic mountain sickness hematologic manifestation by inadequate adaptation to high altitudes of genes regulating erythropoiesis. Statins are inhibitors of the mevalonate pathway involved in the regulation of erythropoiesis. This paper describes the molecular mechanisms of erythropoiesis inhibitionin patients with pathological erythrocytosis. Material and methods We studied 35 patients with pathological erythrocytosis from La Paz and El Alto city (3600 and 4000 masl respectively). Were performed hematopoietic progenitor cell culture and Western blotting. Results Statins induce apoptosis in liquid culture medium. without simvastatin erythroid progenitors from apoptosis presentarón and 12.3% in the group supplemented with simvastatin 38.4% apoptosis (p = 0.001), statins also inhibit the proliferation and differentiation of erythroid progenitors, and inhibit transcription of STAT-5. Conclusions The molecular mechanisms involved in the erythropoiesis inhibition are: a) Inhibition of Ras and Rho isoprenylation, b) Inhibition of Jak-2 and Stat-5 phosphorylation, c) inhibition of EpoR glycosylation, d) Statins reduce lipid rafts cholesterol and reduce JAK2 localization to lipid rafts, e) Induction of apoptosis through caspase 9 and BclxL.