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Lorente L, Martín MM, Pérez-Cejas A, Ramos-Gómez L, Solé-Violan J, Cáceres JJ, Jiménez A, González-Rivero AF. Elevated soluble fas blood concentrations in patients dying from spontaneous intracerebral hemorrhage. World J Crit Care Med 2023; 12:63-70. [PMID: 37034020 PMCID: PMC10075047 DOI: 10.5492/wjccm.v12.i2.63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/09/2022] [Accepted: 02/01/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND Several studies of spontaneous intracerebral hemorrhage (SICH) patients have shown apoptotic changes in brain samples after hematoma evacuation. However, there have been no data on the association between blood concentrations of soluble fas (sFas) (the main surface death receptor of the extrinsic apoptosis pathway) and the prognosis of spontaneous intracranial hypotension (SIH) patients.
AIM To determine whether there is an association between blood sFas concentrations and SICH patient mortality.
METHODS We included patients with severe and supratentorial SIH. Severe was defined as having Glasgow Coma Scale < 9. We determined serum sFas concentrations at the time of severe SICH diagnosis.
RESULTS We found that non-surviving patients (n = 36) compared to surviving patients (n = 39) had higher ICH score (P = 0.001), higher midline shift (P = 0.004), higher serum sFas concentrations (P < 0.001), and lower rate of early hematoma evacuation (P = 0.04). Multiple logistic regression analysis showed an association between serum sFas concentrations and 30-d mortality (odds ratio = 1.070; 95% confidence interval = 1.014-1.129; P = 0.01) controlling for ICH score, midline shift, and early hematoma evacuation.
CONCLUSION The association of blood sFas concentrations and SICH patient mortality is a novel finding in our study.
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Affiliation(s)
- Leonardo Lorente
- Department of Intensive Care, Hospital Universitario de Canarias, La Laguna 38320, Tenerife, Spain
| | - María M Martín
- Department of Intensive Care, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife 38010, Tenerife, Spain
| | - Antonia Pérez-Cejas
- Department of Laboratory, Hospital Universitario de Canarias, La Laguna 38320, Tenerife, Spain
| | - Luis Ramos-Gómez
- Department of Intensive Care, Hospital Universitario de La Palma, Breña Alta 38713, Spain
| | - Jordi Solé-Violan
- Department of Critical Care, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria 35010, Spain
- Department of Critical Care, Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria 35450, Spain
| | - Juan J Cáceres
- Department of Intensive Care, Hospital Insular, Las Palmas de Gran Canaria 35016, Spain
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, La Laguna 38320, Tenerife, Spain
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Lorente L, Martín MM, Pérez-Cejas A, González-Rivero AF, Ramos-Gómez L, Solé-Violán J, Cáceres JJ, Cabrera J, Uribe L, Ferrer-Moure C, Jiménez A. Mortality prediction of patients with spontaneous intracerebral hemorrhage by serum soluble Fas ligand concentrations. Expert Rev Mol Diagn 2021; 22:233-238. [PMID: 34894981 DOI: 10.1080/14737159.2022.2017775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND A study of patients with spontaneous intracerebral hemorrhage (SIH) found a higher content of Fas ligand in the perihematomic brain area compared to healthy brain areas. The objective of this study was to analyze whether blood soluble Fas ligand (sFasL) concentrations could be used to estimate the prognosis of SIH patients. METHODS Observational and prospective study performed in five Spanish Intensive Care Units. Patients with severe supratentorial SIH, defined as Glasgow Coma Scale (GCS) <9, were included. Serum sFasL levels were determined at the time of diagnosis of severe SIH. Mortality at 30 days was the end-point study. RESULTS Surviving SIH patients (n = 41) compared to nonsurvivors (n = 38) showed lower serum sFasL levels (p < 0.001). The area under curve of mortality prediction for serum sFasL levels was 0.79 (95% CI = 0.70-0.89; p < 0.001). Multiple logistic regression analysis found an association of serum sFasL concentrations with 30-day mortality (ORo = 1,034; 95% CI = 1,010-1,058; p = 0,006) after controlling for midline shift, early hematoma evacuation, and intracerebral hemorrhage score. CONCLUSIONS The capability of serum sFasL to predict SIH patient mortality is the main novel finding of our study. ABBREVIATIONS APACHE II: Acute Physiology and Chronic Health Evaluation; aPTT: activated partial thromboplastin time; FIO2: fraction of inspired oxygen; GCS: Glasgow Coma Scale; ICU: Intensive Care Unit; INR: international normalized ratio; PaO2: pressure of arterial oxygen.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, La Laguna Santa Cruz de Tenerife, Spain
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Antonia Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | | | | | - Jordi Solé-Violán
- Intensive Care Unit, Hospital Universitario Dr. Negrín. CIBERES, Las Palmas de Gran Canaria, Spain
| | - Juan J Cáceres
- Intensive Care Unit, Hospital Insular, Las Palmas de Gran Canaria, Spain
| | - Judith Cabrera
- Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Luis Uribe
- Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Carmen Ferrer-Moure
- Laboratory Department, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, La Laguna. Santa Cruz de Tenerife, Spain
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Lorente L, Martín MM, González-Rivero AF, Ramos-Gómez L, Sole-Violan J, Cáceres JJ, Villacampa-Jiménez JJ, Jiménez A, Pérez-Cejas A. Mortality of spontaneous intracerebral haemorrhage patients and high serum caspase-8 concentrations. Anaesth Crit Care Pain Med 2021; 40:100969. [PMID: 34718185 DOI: 10.1016/j.accpm.2021.100969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/14/2021] [Accepted: 09/11/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Apoptotic changes in brain samples have been found in haematoma areas of patients with spontaneous intracerebral haemorrhage (SIH) undergoing surgical haematoma evacuation. However, circulating caspase-8 concentrations in SIH patients have not been described. Thus, we carried out this study with the aim to explore whether there is an association of circulating caspase-8 concentrations and mortality in patients with SIH. METHODS We included patients with severe and supratentorial SIH. We established that the SIH was severe if Glasgow Coma Scale (GCS) was lower than 9. Intensive Care Units from 5 Spanish hospitals carried out the recruitment of patients of this observational and prospective study. We registered serum caspase-8 levels at moment of severe SIH diagnosis and 30-day mortality. RESULTS Surviving (n = 41) in respect to non-surviving SIH patients (n = 38) showed lower serum caspase-8 levels (p < 0.001). The area under the curve to estimate 30-day mortality ability by serum caspase-8 levels was 0.75 (95% CI = 0.64-86; p < 0.001). Kaplan-Meier analysis found that patients with serum caspase-8 levels > 17.8 ng/mL showed higher death risk (Hazard ratio = 3.9; 95% CI = 1.99-7.63; p < 0.001). Multiple logistic regression analysis revealed the association of serum caspase-8 concentrations (controlling for intracerebral haemorrhage score, midline shift and early haematoma evacuation) with mortality at 30 days (Odds Ratio = 1.048; 95% CI = 1.018-1.079; p = 0.002). CONCLUSIONS The association of serum caspase-8 concentrations with mortality of SIH patient mortality is the main of novel findings that have been revealed in our study.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n, La Laguna, Santa Cruz de Tenerife 38320, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Crta del Rosario s/n, Santa Cruz de Tenerife 38010, Spain
| | - Agustín F González-Rivero
- Laboratory Department, Hospital Universitario de Canarias, Ofra s/n, La Laguna, Santa Cruz de Tenerife 38320, Spain
| | - Luis Ramos-Gómez
- Intensive Care Unit, Hospital General La Palma, Buenavista de Arriba s/n, Breña Alta, La Palma 38713, Spain
| | - Jordi Sole-Violan
- Intensive Care Unit, Hospital Universitario Dr. Negrín, CIBERES, Barranco de la Ballena s/n, Las Palmas de Gran Canaria 35010, Spain
| | - Juan J Cáceres
- Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, Las Palmas de Gran Canaria 35016, Spain
| | | | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra s/n, La Laguna, Santa Cruz de Tenerife 38320, Spain
| | - Antonia Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320 Tenerife, Spain
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Lorente L, Martín MM, González-Rivero AF, Pérez-Cejas A, Ramos-Gómez L, Cáceres JJ, Solé-Violán J, Villacampa-Jiménez JJ, Jiménez A. Serum B cell lymphoma-2 concentrations and mortality of patients with spontaneous intracerebral hemorrhage. Neurol Sci 2021; 42:3631-3636. [PMID: 33433754 DOI: 10.1007/s10072-021-05048-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/06/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVE There is scarce data on B cell lymphoma 2 (Bcl2), a member of the Bcl-2 family of antiapoptotic molecules of the intrinsic apoptosis pathway, in patients with spontaneous intracerebral hemorrhage (SIH). In one study, higher serum Bcl2 levels were found in patients with SIH than in healthy subjects. Thus, the objective of our study was to compare serum Bcl2 levels in surviving and non-surviving SIH patients. METHODS Patients with severe supratentorial SIH (defined as Glasgow Coma Scale < 9) admitted from the Intensive Care Units of five Spanish hospitals were included in this observational and prospective study. Serum levels of Bcl2L were determined at the time of diagnosis. Thirty-day mortality was the end-point study. RESULTS Non-surviving (n = 38) compared to surviving patients (n = 41) had higher intracerebral hemorrhage (ICH) score (p = 0.001), midline shift (p = 0.003), and serum Bcl2 levels (p < 0.001). In addition, non-surviving compared to surviving patients had lower early hematoma evacuation rate (p = 0.03). We found 77% area under curve in mortality prediction for serum Bcl2 levels (95% CI = 0.66-88%; p < 0.001). Patients showing serum Bcl2 levels > 16.5 ng/mL had higher risk of death according to analysis of Kaplan-Meier (HR = 5.2; 95% CI = 2.5-10.6; p < 0.001). An association, after control for ICH score, midline shift, and early hematoma evacuation, was found between serum Bcl2 levels and 30-day mortality (OR = 1.090; 95% CI = 1.030-1.154; p = 0.003) in the multiple logistic regression. CONCLUSIONS As far as we know, our study is the first one reporting higher serum Bcl2 levels in non-surviving than in surviving SIH patients and the association between serum Bcl2 levels and SIH mortality.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n, La Laguna, 38320, Santa Cruz de Tenerife, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Crta del Rosario s/n, 38010, Santa Cruz de Tenerife, Spain
| | - Agustín F González-Rivero
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320, Santa Cruz de Tenerife, Spain
| | - Antonia Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320, Santa Cruz de Tenerife, Spain
| | - Luis Ramos-Gómez
- Intensive Care Unit, Hospital General La Palma, Buenavista de Arriba s/n, La Palma, 38713, Breña Alta, Spain
| | - Juan J Cáceres
- Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, 35016, Las Palmas de Gran Canaria, Spain
| | - Jordi Solé-Violán
- Intensive Care Unit, Hospital Universitario Dr. Negrín, CIBERES, Barranco de la Ballena s/n, 35010, Las Palmas de Gran Canaria, Spain
| | - Jacobo J Villacampa-Jiménez
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320, Santa Cruz de Tenerife, Spain
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra s/n, La Laguna, 38320, Santa Cruz de Tenerife, Spain
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Zhou ZY, Zhao WR, Xiao Y, Zhang J, Tang JY, Lee SMY. Mechanism Study of the Protective Effects of Sodium Tanshinone IIA Sulfonate Against Atorvastatin-Induced Cerebral Hemorrhage in Zebrafish: Transcriptome Analysis. Front Pharmacol 2020; 11:551745. [PMID: 33123006 PMCID: PMC7567336 DOI: 10.3389/fphar.2020.551745] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 09/10/2020] [Indexed: 12/11/2022] Open
Abstract
Hemorrhage stroke is a severe vascular disease of the brain with a high mortality rate in humans. Salvia miltiorrhiza Bunge (Danshen) is a well-known Chinese Materia Medica for treating cerebral vascular and cardiovascular diseases in traditional Chinese medicine. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, which is the main active ingredient of Danshen. In our previous study, we established a zebrafish model of cerebral hemorrhage and found that STS dramatically decreased both the hemorrhage rate and hemorrhage area, although the underlying mechanism was not fully elucidated. We conducted a transcriptome analysis of the protective effect of STS against atorvastatin (Ator)-induced cerebral hemorrhage in zebrafish using RNA-seq technology. RNA-seq revealed 207 DEGs between the Ator-treated group and control group; the expression levels of 53 DEGs between the Ator-treated group and control group were reversed between the STS + Ator-treated group and Ator-treated group. GO enrichment analysis indicated that these 53 DEGs encode proteins with roles in hemoglobin complexes, oxygen carrier activity and oxygen binding, etc. KEGG analysis suggested that these 53 DEGs were most enriched in three items, namely, porphyrin and chlorophyll metabolism, ferroptosis, and the HIF-1 signaling pathway. The PPI network analysis identified 12 hub genes, and we further verified that Ator elevated the mRNA expression levels of hemoglobin (hbae1.3, hbae3, hbae5, hbbe2, and hbbe3), carbonic anhydrase (cahz), HIF-1 (hif1al2) and Na+/H+ exchanger (slc4a1a and slc9a1) genes, while STS significantly suppressed these genes. In addition, we found that pharmacological inhibition of PI3K/Akt, MAPKs, and mTOR signaling pathways by specific inhibitors partially attenuated the protective effect of STS against Ator-induced cerebral hemorrhage in zebrafish, regardless of mTOR inhibition. We concluded that hemoglobin, carbonic anhydrase, Na+/H+ exchanger and HIF-1 genes might be potential biomarkers of Ator-induced cerebral hemorrhage in zebrafish, as well as pharmacological targets of STS. Moreover, HIF-1 and its regulators, i.e., the PI3K/Akt and MAPK signaling pathways, were involved in the protective effect of STS against Ator-induced cerebral hemorrhage. This study also provided evidence of biomarkers involved in hemorrhage stroke and improved understanding of the effects of HMG-COA reductase inhibition on vascular permeability and cerebral hemorrhage.
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Affiliation(s)
- Zhong-Yan Zhou
- Department of Cardiovascular Research Laboratory, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Wai-Rong Zhao
- Department of Cardiovascular Research Laboratory, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Xiao
- Department of Cardiovascular Research Laboratory, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Zhang
- Department of Cardiovascular Research Laboratory, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing-Yi Tang
- Department of Cardiovascular Research Laboratory, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Simon Ming-Yuen Lee
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China
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High Serum Levels of Caspase-3 and Early Mortality in Patients with Severe Spontaneous Intracerebral Hemorrhage. Neurocrit Care 2020; 34:175-181. [PMID: 32514709 DOI: 10.1007/s12028-020-01012-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
BACKGROUND Apoptotic cell death leads to secondary brain injury after spontaneous intracerebral hemorrhage (SIH). There is an association between serum caspase-3 levels and late mortality (at 6 months) in patients with SIH in basal ganglia. The new objective of this study was to determine whether there exists an association between serum caspase-3 levels and early mortality (at 30 days) in patients with SIH at different sites and not only in basal ganglia. METHODS Patients with severe supratentorial SIH (defined as Glasgow Coma Scale < 9) admitted in 6 Spanish hospitals were included in this observational and prospective study. Patients with SIH due to aneurysm, arteriovenous malformation, and anticoagulant or fibrinolytic treatment were excluded. Serum caspase-3 levels at days 1, 4, and 8 of SIH were determined. Thirty-day mortality was the end-point study. RESULTS Non-surviving (n = 53) showed higher serum caspase-3 levels at days 1 (p < 0.001), 4 (p < 0.001), and 8 (p < 0.001) than survivor patients (n = 64). Multiple logistic regression analysis showed an association of serum caspase-3 levels > 0.167 ng/mL with 30-day mortality (Odds Ratio = 47.007; 95% CI = 4.838-456.727; p = 0.001). CONCLUSIONS The new findings of our study are that serum caspase-3 levels are associated with early mortality in patients with severe supratentorial SIH at different sites and that those levels during the first week of SIH are higher in non-survivors than in survivors.
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Lorente L, Martín MM, Pérez-Cejas A, Ramos L, Argueso M, Solé-Violán J, Cáceres JJ, Jiménez A, García-Marín V. Association between serum levels of caspase-cleaved cytokeratin-18 and early mortality in patients with severe spontaneous intracerebral hemorrhage. BMC Neurosci 2018; 19:23. [PMID: 29661155 PMCID: PMC5902924 DOI: 10.1186/s12868-018-0424-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 04/06/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Apoptotic changes after cerebral hemorrhage in brain samples of humans have been found. Caspase-cleaved cytokeratin (CCCK)-18 could be detected in the bloodstream during apoptosis. Higher circulating CCCK-18 levels have been associated with 6-month mortality in patients with basal ganglia hemorrhage. The aim of our study was to determine whether there is an association between serum CCCK-18 levels and early mortality of spontaneous intracerebral hemorrhage (SIH) patients. We performed an observational, prospective and multicentre study. There were included patients with severe SIH defined as Glasgow Coma Scale (GCS) lower than 9. We determined serum CCCK-18 levels at the severe SIH diagnosis moment. RESULTS We found that non-surviving SIH patients (n = 46) showed lower GCS, and higher serum CCCK-18 levels and APACHE-II score than survivor ones (n = 54). In ROC analysis was found that the area under the curve of serum CCCK-18 levels for 30-day mortality prediction was 90% (95% CI 82-95%; p < 0.001). In the multiple logistic regression analysis, we found an association between serum CCCK-18 levels and 30-day mortality (OR 1.034; 95% CI 1.013-1.055; p = 0.002). CONCLUSIONS The novel finding of our study was that there is an association between high serum CCCK-18 levels and 30-day mortality in severe SIH patients.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320, Santa Cruz de Tenerife, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Crta del Rosario s/n, 38010, Santa Cruz de Tenerife, Spain
| | - Antonia Pérez-Cejas
- Laboratory Department, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320, Santa Cruz de Tenerife, Spain
| | - Luis Ramos
- Intensive Care Unit, Hospital General La Palma, Buenavista de Arriba s/n, Breña Alta, 38713, La Palma, Spain
| | - Mónica Argueso
- Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avda. Blasco Ibáñez no 17-19, 46004, Valencia, Spain
| | - Jordi Solé-Violán
- Intensive Care Unit, Hospital Universitario Dr. Negrín, CIBERES, Barranco de la Ballena s/n, 35010, Las Palmas de Gran Canaria, Spain
| | - Juan J Cáceres
- Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, 35016, Las Palmas de Gran Canaria, Spain
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320, Santa Cruz de Tenerife, Spain
| | - Victor García-Marín
- Department of Neurosurgery, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320, Santa Cruz de Tenerife, Spain
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Chen W, Ostrowski RP, Obenaus A, Zhang JH. Prodeath or prosurvival: two facets of hypoxia inducible factor-1 in perinatal brain injury. Exp Neurol 2008; 216:7-15. [PMID: 19041643 DOI: 10.1016/j.expneurol.2008.10.016] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2008] [Revised: 09/12/2008] [Accepted: 10/24/2008] [Indexed: 01/13/2023]
Abstract
Hypoxia, which occurs in the brain when oxygen availability drops below the normal level, is a major cause of perinatal hypoxic-ischemic injury (HII). The transcriptional factor hypoxia inducible factor-1 (HIF-1) is a key regulator in the pathophysiological response to the stress of hypoxia. Genes regulated by HIF-1 are involved in energy metabolism, erythropoiesis, angiogenesis, vasodilatation, cell survival and apoptosis. Compared with the adult brain, the neonatal brain is different in physiological structure, function, cellular composition and signaling pathway related gene activation and response after hypoxia. The purpose of this review is to determine if developmental susceptibility of the brain after hypoxic/ischemic injury is related to HIF-1alpha, which also plays a pivotal role in the normal brain development. HIF-1alpha regulates both prosurvival and prodeath responses in the neonatal brain and various mechanisms underlie the apparent contradictory effects, including duration of ischemic injury and severity, cell-types, and/or dependent on the nature of the stimulus after HII. Studies report an excessive induction of HIF-1 in the immature brain, which suggests that a cell death promoting role of HIF may prevail. Inhibition of HIF-1alpha and targeted activation of its prosurvival genes appear as a favorable therapeutic strategy. However, a better understanding of multifaceted HIF-1 function during brain development is required to explore potential targets for further therapeutic interventions in the neonate.
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Affiliation(s)
- Wanqiu Chen
- Department of Physiology, Loma Linda University, Loma Linda, CA 92354, USA
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