European Journal of Vascular and Endovascular Surgery, 2022
Intracranial endovascular thrombectomy (EVT) has revolutionised the care of patients with large v... more Intracranial endovascular thrombectomy (EVT) has revolutionised the care of patients with large vessel acute ischaemic stroke, reducing long term disability, but little is known about how to treat residual concomitant extracranial carotid stenosis. The present study is the first relatively large cohort study on patients treated with carotid endarterectomy (CEA) after successful EVT. Although the results are preliminary, and pending larger studies, and ideally a randomised controlled trial comparing CEA with stenting, it seems safe. Except in cases of large cerebral infarction, CEA can be performed early after EVT, without increased risk of post-operative stroke or death. Objective: Recent randomised controlled trials demonstrated the benefit of intracranial endovascular thrombectomy (EVT) in acute ischaemic stroke.There is no consensus, however, on how to treat concomitant extracranial carotid artery stenosis after EVT. The aim of this study was to evaluate the outcome in patients treated with carotid endarterectomy (CEA) after EVT, comparing complication rates among patients undergoing CEA for stroke without previous EVT. Methods: This was a registry study of all patients (n ¼ 3 780) treated with CEA after stroke in Sweden and the capital Helsinki region, Finland, from January 2011 to September 2020. Sixty three patients (1.7%; 0.5% 2011, 4.3% 2019) underwent EVT prior to CEA. The primary outcome was 30 day stroke and death rate. Results: The EVTþCEA group had major stroke as the qualifying neurological event (QNE) in 79%, but just 5.9% had this in the CEA only group (p < .001). Intravenous thrombolysis was administered before EVT in 54% of patients in the EVTþCEA group, but in just 12% in those receiving CEA only (p < .001). The combined stroke and death rate at 30 days for EVTþCEA was 0.0% (95% confidence interval [CI] 0.0 e 5.7). One patient had a post-operative TIA, none had post-operative intracerebral or surgical site haemorrhage. CEA was performed within a median of seven days (interquartile range 4, 15) after QNE, and 75% had CEA 14 days from QNE. The main reason to postpone CEA was an infarct larger than one third of the middle cerebral artery territory. The stroke and death rate in patients treated with CEA only was 3.7% (95% CI 3.2 e 4.4), CEA was performed a median of eight days after QNE, and in 79.7% in 14 days. The three year survival after EVTþCEA was 93% (95% CI 85 e 100), compared with 87% (95% CI 86 e 88) after CEA only. Cox regression analysis adjusting for age showed no increased all cause mortality after EVTþCEA (HR 1.3, 95% CI 0.6 e 2.7, p ¼ .52). Conclusion: These results indicate that CEA is safe to perform after previous successful EVT for acute ischaemic stroke. Results were comparable with those undergoing CEA only, despite the EVTþCEA patients having more severe stroke symptoms prior to surgery, and timing was similar.
Aro, Ellinoora, Prolyl 4-hydroxylases, key enzymes regulating hypoxia response and collagen synth... more Aro, Ellinoora, Prolyl 4-hydroxylases, key enzymes regulating hypoxia response and collagen synthesis. The roles of specific isoenzymes in the control of erythropoiesis and skeletogenesis
Objective: Based on our previous reports, ipsilateral systolic toe pressure (STP) and toe-brachia... more Objective: Based on our previous reports, ipsilateral systolic toe pressure (STP) and toe-brachial index (TBI) have a strong association with midterm cardiovascular and overall mortality as well as with amputation-free survival in patients with symptomatic lower extremity peripheral artery disease (PAD). The effect of the often overlooked contralateral lower limb on patient outcome remains unknown. This study aimed to resolve the significance of contralateral STP (CL_STP) and contralateral TBI for long-term overall and cardiovascular mortality. Methods: This is a retrospective cohort study of 727 consecutive patients with symptomatic lower extremity PAD. All patients admitted to the Department of Vascular Surgery at Turku University Hospital for digital subtraction angiography between January 2009 and August 2011 and for whom STP measurements were available were recruited and observed for up to 7 years. Dates and causes of death were collected from the national cause of death registry of Statistics Finland. Results: In the study cohort, STP was <30 mm Hg in 67 contralateral limbs and 227 ipsilateral limbs. CL_STP <30 mm Hg resulted in a 60-month estimated freedom from cardiovascular death and overall survival of 39% (standard deviation [SD], 0.57) and 25% (SD, 0.41), respectively, and contralateral TBI <0.25, of 45% (SD, 0.54) and 36% (SD, 0.54), respectively. Cumulative freedom from cardiovascular death and overall survival at 60 months for patients with ipsilateral STP <30 mm Hg varied by CL_STP as follows: CL_STP <30 mm Hg: 41% (SD, 0.58) and 25% (SD, 0.43); CL_STP of 30 to 49 mm Hg: 56% (SD, 0.49) and 44% (SD, 0.49); STP $50 mm Hg: 62% (SD, 0.52) and 47% (SD, 0.52), respectively. In Cox regression analysis, low STP or TBI of either extremity was associated with significant (P < .001) risk of death for cardiovascular or any reason. Conclusions: Low STP and TBI of both contralateral and ipsilateral lower extremities are associated with high cardiovascular and overall mortality in symptomatic PAD patients. Bilaterally low STP and TBI are associated with a particularly poor prognosis.
Background and Purpose-Carotid endarterectomy (CEA) is recommended within 14 days after carotid a... more Background and Purpose-Carotid endarterectomy (CEA) is recommended within 14 days after carotid artery stroke to prevent recurrence. However, the optimal timing of CEA after intravenous thrombolysis (IVT) remains unclear. We studied the safety of CEA after IVT while taking into account both stroke recurrence and CEA-related complications. Methods-Patients who underwent IVT followed by CEA in Helsinki University Hospital 2005 to 2016 were withdrawn from prospectively collected registers. The incidence of stroke recurrence during the time between IVT and CEA, peri/ postoperative stroke, hyperperfusion syndrome or drug-resistant high blood pressure, and 3-month outcome measured by modified Rankin Scale was recorded. Stroke patients treated with CEA without preceding IVT were used as controls. Results-Altogether 128 CEAs with preceding IVT and 777 CEAs for stroke without IVT were identified. The median time from IVT to CEA was 9 days (range, 0-349 days; interquartile range, 16). Seven patients (5.5%) underwent CEA within 24 hours, 20 (15.6%) within 48 hours and 87 (68.0%) within 2 weeks from IVT. Stroke recurrence in IVT-CEA patients was 5.5% at median 4 days after IVT (range, 0-8 days). Outcome from CEAs performed within 48 hours from IVT did not differ from CEAs performed later with respect to peri/postoperative ischemic strokes (5.0% and 3.7%), hemorrhagic strokes (5.0% and 1.9%), neck hematomas (5.0% and 8.3%), myocardial infarctions (0.0% and 0.9%), or 3-month modified Rankin Scale. There was a tendency toward higher incidence of hyperperfusion syndrome in the patients operated within 48 hours from IVT (20.0% versus 6.5%; P=0.070). The CEA-related stroke rate was similar to that of the operation without thrombolysis. Only smoking was significantly associated with peri/postoperative stroke (odds ratio, 21.82; 95% confidence interval, 1.08-439.58). Conclusions-Time between IVT and CEA was not associated with CEA-related complications. The high rate of stroke recurrence during the waiting time for CEA underscores the importance of shortening surgery delays.
Traditionally, acute evacuations of traumatic intracranial hematomas are performed by neurosurgeo... more Traditionally, acute evacuations of traumatic intracranial hematomas are performed by neurosurgeons in university hospitals. However, most patients with traumatic brain injury are initially transported to regional hospitals that lack neurosurgical expertise. Thus, a trauma surgeon in a regional hospital may encounter a patient with an expanding hematoma that must be operated without delays. During 2006 to 2014, 14 craniotomies were performed at the North Karelia Central Hospital. Twelve patients were operated for acute traumatic subdural hematoma (ASDH): three patients made good recovery, two were left with severe disability, and seven died. Two patients operated with acute epidural hematoma (EDH) recovered well.
Background: Roles of collagen prolyl 4-hydroxylases (C-P4Hs) I and II in growth plate development... more Background: Roles of collagen prolyl 4-hydroxylases (C-P4Hs) I and II in growth plate development were studied. Results: Proliferating chondrocytes undergo apoptosis in C-P4H-I ϩ/Ϫ ;C-P4H-II Ϫ/Ϫ growth plates, and the mice develop chondrodysplasia. Conclusion: Biomechanically impaired extracellular matrix is the primary cause of death of C-P4H-I ϩ/Ϫ ;C-P4H-II Ϫ/Ϫ growth plate chondrocytes. Significance: Sufficient C-P4H activity is essential for growth plate chondrocyte survival and proper skeletogenesis. Collagen prolyl 4-hydroxylases (C-P4H-I, C-P4H-II, and C-P4H-III) catalyze formation of 4-hydroxyproline residues required to form triple-helical collagen molecules. Vertebrate C-P4Hs are ␣ 2  2 tetramers differing in their catalytic ␣ subunits. C-P4H-I is the major isoenzyme in most cells, and inactivation of its catalytic subunit (P4ha1 ؊/؊) leads to embryonic lethality in mouse, whereas P4ha1 ؉/؊ mice have no abnormalities. To study the role of C-P4H-II, which predominates in chondrocytes, we generated P4ha2 ؊/؊ mice. Surprisingly, they had no apparent phenotypic abnormalities. To assess possible functional complementarity, we established P4ha1 ؉/؊ ;P4ha2 ؊/؊ mice. They were smaller than their littermates, had moderate chondrodysplasia, and developed kyphosis. A transient inner cell death phenotype was detected in their developing growth plates. The columnar arrangement of proliferative chondrocytes was impaired, the amount of 4-hydroxyproline and the T m
Background: The hypoxic cartilaginous growth plate is rich in extracellular matrix (ECM). Results... more Background: The hypoxic cartilaginous growth plate is rich in extracellular matrix (ECM). Results: Expression of the key enzymes in ECM synthesis, the collagen prolyl 4-hydroxylases (C-P4Hs), is induced specifically by hypoxia-inducible factor 1. Conclusion: Hypoxia inducibility of C-P4Hs ensures sufficient C-P4H activity in hypoxic chondrocytes. Significance: Quantitative regulation of C-P4H may be a key modality by which hypoxia influences early chondrocyte survival and differentiation. Hypoxia-inducible factors (HIFs) are the master regulators of hypoxia-responsive genes. They play a critical role in the survival, development, and differentiation of chondrocytes in the avascular hypoxic fetal growth plate, which is rich in extracellular matrix (ECM) and in its main component, collagens. Several genes involved in the synthesis, maintenance, and degradation of ECM are regulated by HIFs. Collagen prolyl 4-hydroxylases (C-P4Hs) are key enzymes in collagen synthesis because the resulting 4-hydroxyprolines are necessary for the stability of all collagen molecules. The vertebrate C-P4Hs are ␣ 2  2 tetramers with three isoforms of the catalytic ␣ subunit, yielding C-P4Hs of types I-III. C-P4H-I is the main form in most cells, but C-P4H-II is the major form in chondrocytes. We postulated here that post-translational modification of collagens, particularly 4-hydroxylation of proline residues, could be one of the modalities by which HIF regulates the adaptive responses of chondrocytes in fetal growth plates. To address this hypothesis, we used primary epiphyseal growth plate chondrocytes isolated from newborn mice with conditionally inactivated genes for HIF-1␣, HIF-2␣, or the von Hippel-Lindau protein. The data obtained showed that C-P4H ␣(I) and ␣(II) mRNA levels were increased in hypoxic chondrocytes in a manner dependent on HIF-1 but not on HIF-2. Furthermore, the increases in the C-P4H mRNA levels were associated with both increased amounts of the C-P4H tetramers and augmented C-P4H activity in hypoxia. The hypoxia inducibility of the C-P4H isoenzymes is thus likely to ensure sufficient C-P4H activity for collagen synthesis occurring in chondrocytes in a hypoxic environment.
An endoplasmic reticulum transmembrane prolyl 4-hydroxylase (P4H-TM) is able to hydroxylate the α... more An endoplasmic reticulum transmembrane prolyl 4-hydroxylase (P4H-TM) is able to hydroxylate the α subunit of the hypoxia-inducible factor (HIF) in vitro and in cultured cells, but nothing is known about its roles in mammalian erythropoiesis. We studied such roles here by administering a HIF-P4H inhibitor, FG-4497, to P4h-tm−/− mice. This caused larger increases in serum Epo concentration and kidney but not liver Hif-1α and Hif-2α protein and Epo mRNA levels than in wild-type mice, while the liver Hepcidin mRNA level was lower in the P4h-tm−/− mice than in the wild-type. Similar, but not identical, differences were also seen between FG-4497–treated Hif-p4h-2 hypomorphic (Hif-p4h-2gt/gt) and Hif-p4h-3−/− mice versus wild-type mice. FG-4497 administration increased hemoglobin and hematocrit values similarly in the P4h-tm−/− and wild-type mice, but caused higher increases in both values in the Hif-p4h-2gt/gt mice and in hematocrit value in the Hif-p4h-3−/− mice than in the wild-type. Hi...
European Journal of Vascular and Endovascular Surgery, 2022
Intracranial endovascular thrombectomy (EVT) has revolutionised the care of patients with large v... more Intracranial endovascular thrombectomy (EVT) has revolutionised the care of patients with large vessel acute ischaemic stroke, reducing long term disability, but little is known about how to treat residual concomitant extracranial carotid stenosis. The present study is the first relatively large cohort study on patients treated with carotid endarterectomy (CEA) after successful EVT. Although the results are preliminary, and pending larger studies, and ideally a randomised controlled trial comparing CEA with stenting, it seems safe. Except in cases of large cerebral infarction, CEA can be performed early after EVT, without increased risk of post-operative stroke or death. Objective: Recent randomised controlled trials demonstrated the benefit of intracranial endovascular thrombectomy (EVT) in acute ischaemic stroke.There is no consensus, however, on how to treat concomitant extracranial carotid artery stenosis after EVT. The aim of this study was to evaluate the outcome in patients treated with carotid endarterectomy (CEA) after EVT, comparing complication rates among patients undergoing CEA for stroke without previous EVT. Methods: This was a registry study of all patients (n ¼ 3 780) treated with CEA after stroke in Sweden and the capital Helsinki region, Finland, from January 2011 to September 2020. Sixty three patients (1.7%; 0.5% 2011, 4.3% 2019) underwent EVT prior to CEA. The primary outcome was 30 day stroke and death rate. Results: The EVTþCEA group had major stroke as the qualifying neurological event (QNE) in 79%, but just 5.9% had this in the CEA only group (p < .001). Intravenous thrombolysis was administered before EVT in 54% of patients in the EVTþCEA group, but in just 12% in those receiving CEA only (p < .001). The combined stroke and death rate at 30 days for EVTþCEA was 0.0% (95% confidence interval [CI] 0.0 e 5.7). One patient had a post-operative TIA, none had post-operative intracerebral or surgical site haemorrhage. CEA was performed within a median of seven days (interquartile range 4, 15) after QNE, and 75% had CEA 14 days from QNE. The main reason to postpone CEA was an infarct larger than one third of the middle cerebral artery territory. The stroke and death rate in patients treated with CEA only was 3.7% (95% CI 3.2 e 4.4), CEA was performed a median of eight days after QNE, and in 79.7% in 14 days. The three year survival after EVTþCEA was 93% (95% CI 85 e 100), compared with 87% (95% CI 86 e 88) after CEA only. Cox regression analysis adjusting for age showed no increased all cause mortality after EVTþCEA (HR 1.3, 95% CI 0.6 e 2.7, p ¼ .52). Conclusion: These results indicate that CEA is safe to perform after previous successful EVT for acute ischaemic stroke. Results were comparable with those undergoing CEA only, despite the EVTþCEA patients having more severe stroke symptoms prior to surgery, and timing was similar.
Aro, Ellinoora, Prolyl 4-hydroxylases, key enzymes regulating hypoxia response and collagen synth... more Aro, Ellinoora, Prolyl 4-hydroxylases, key enzymes regulating hypoxia response and collagen synthesis. The roles of specific isoenzymes in the control of erythropoiesis and skeletogenesis
Objective: Based on our previous reports, ipsilateral systolic toe pressure (STP) and toe-brachia... more Objective: Based on our previous reports, ipsilateral systolic toe pressure (STP) and toe-brachial index (TBI) have a strong association with midterm cardiovascular and overall mortality as well as with amputation-free survival in patients with symptomatic lower extremity peripheral artery disease (PAD). The effect of the often overlooked contralateral lower limb on patient outcome remains unknown. This study aimed to resolve the significance of contralateral STP (CL_STP) and contralateral TBI for long-term overall and cardiovascular mortality. Methods: This is a retrospective cohort study of 727 consecutive patients with symptomatic lower extremity PAD. All patients admitted to the Department of Vascular Surgery at Turku University Hospital for digital subtraction angiography between January 2009 and August 2011 and for whom STP measurements were available were recruited and observed for up to 7 years. Dates and causes of death were collected from the national cause of death registry of Statistics Finland. Results: In the study cohort, STP was <30 mm Hg in 67 contralateral limbs and 227 ipsilateral limbs. CL_STP <30 mm Hg resulted in a 60-month estimated freedom from cardiovascular death and overall survival of 39% (standard deviation [SD], 0.57) and 25% (SD, 0.41), respectively, and contralateral TBI <0.25, of 45% (SD, 0.54) and 36% (SD, 0.54), respectively. Cumulative freedom from cardiovascular death and overall survival at 60 months for patients with ipsilateral STP <30 mm Hg varied by CL_STP as follows: CL_STP <30 mm Hg: 41% (SD, 0.58) and 25% (SD, 0.43); CL_STP of 30 to 49 mm Hg: 56% (SD, 0.49) and 44% (SD, 0.49); STP $50 mm Hg: 62% (SD, 0.52) and 47% (SD, 0.52), respectively. In Cox regression analysis, low STP or TBI of either extremity was associated with significant (P < .001) risk of death for cardiovascular or any reason. Conclusions: Low STP and TBI of both contralateral and ipsilateral lower extremities are associated with high cardiovascular and overall mortality in symptomatic PAD patients. Bilaterally low STP and TBI are associated with a particularly poor prognosis.
Background and Purpose-Carotid endarterectomy (CEA) is recommended within 14 days after carotid a... more Background and Purpose-Carotid endarterectomy (CEA) is recommended within 14 days after carotid artery stroke to prevent recurrence. However, the optimal timing of CEA after intravenous thrombolysis (IVT) remains unclear. We studied the safety of CEA after IVT while taking into account both stroke recurrence and CEA-related complications. Methods-Patients who underwent IVT followed by CEA in Helsinki University Hospital 2005 to 2016 were withdrawn from prospectively collected registers. The incidence of stroke recurrence during the time between IVT and CEA, peri/ postoperative stroke, hyperperfusion syndrome or drug-resistant high blood pressure, and 3-month outcome measured by modified Rankin Scale was recorded. Stroke patients treated with CEA without preceding IVT were used as controls. Results-Altogether 128 CEAs with preceding IVT and 777 CEAs for stroke without IVT were identified. The median time from IVT to CEA was 9 days (range, 0-349 days; interquartile range, 16). Seven patients (5.5%) underwent CEA within 24 hours, 20 (15.6%) within 48 hours and 87 (68.0%) within 2 weeks from IVT. Stroke recurrence in IVT-CEA patients was 5.5% at median 4 days after IVT (range, 0-8 days). Outcome from CEAs performed within 48 hours from IVT did not differ from CEAs performed later with respect to peri/postoperative ischemic strokes (5.0% and 3.7%), hemorrhagic strokes (5.0% and 1.9%), neck hematomas (5.0% and 8.3%), myocardial infarctions (0.0% and 0.9%), or 3-month modified Rankin Scale. There was a tendency toward higher incidence of hyperperfusion syndrome in the patients operated within 48 hours from IVT (20.0% versus 6.5%; P=0.070). The CEA-related stroke rate was similar to that of the operation without thrombolysis. Only smoking was significantly associated with peri/postoperative stroke (odds ratio, 21.82; 95% confidence interval, 1.08-439.58). Conclusions-Time between IVT and CEA was not associated with CEA-related complications. The high rate of stroke recurrence during the waiting time for CEA underscores the importance of shortening surgery delays.
Traditionally, acute evacuations of traumatic intracranial hematomas are performed by neurosurgeo... more Traditionally, acute evacuations of traumatic intracranial hematomas are performed by neurosurgeons in university hospitals. However, most patients with traumatic brain injury are initially transported to regional hospitals that lack neurosurgical expertise. Thus, a trauma surgeon in a regional hospital may encounter a patient with an expanding hematoma that must be operated without delays. During 2006 to 2014, 14 craniotomies were performed at the North Karelia Central Hospital. Twelve patients were operated for acute traumatic subdural hematoma (ASDH): three patients made good recovery, two were left with severe disability, and seven died. Two patients operated with acute epidural hematoma (EDH) recovered well.
Background: Roles of collagen prolyl 4-hydroxylases (C-P4Hs) I and II in growth plate development... more Background: Roles of collagen prolyl 4-hydroxylases (C-P4Hs) I and II in growth plate development were studied. Results: Proliferating chondrocytes undergo apoptosis in C-P4H-I ϩ/Ϫ ;C-P4H-II Ϫ/Ϫ growth plates, and the mice develop chondrodysplasia. Conclusion: Biomechanically impaired extracellular matrix is the primary cause of death of C-P4H-I ϩ/Ϫ ;C-P4H-II Ϫ/Ϫ growth plate chondrocytes. Significance: Sufficient C-P4H activity is essential for growth plate chondrocyte survival and proper skeletogenesis. Collagen prolyl 4-hydroxylases (C-P4H-I, C-P4H-II, and C-P4H-III) catalyze formation of 4-hydroxyproline residues required to form triple-helical collagen molecules. Vertebrate C-P4Hs are ␣ 2  2 tetramers differing in their catalytic ␣ subunits. C-P4H-I is the major isoenzyme in most cells, and inactivation of its catalytic subunit (P4ha1 ؊/؊) leads to embryonic lethality in mouse, whereas P4ha1 ؉/؊ mice have no abnormalities. To study the role of C-P4H-II, which predominates in chondrocytes, we generated P4ha2 ؊/؊ mice. Surprisingly, they had no apparent phenotypic abnormalities. To assess possible functional complementarity, we established P4ha1 ؉/؊ ;P4ha2 ؊/؊ mice. They were smaller than their littermates, had moderate chondrodysplasia, and developed kyphosis. A transient inner cell death phenotype was detected in their developing growth plates. The columnar arrangement of proliferative chondrocytes was impaired, the amount of 4-hydroxyproline and the T m
Background: The hypoxic cartilaginous growth plate is rich in extracellular matrix (ECM). Results... more Background: The hypoxic cartilaginous growth plate is rich in extracellular matrix (ECM). Results: Expression of the key enzymes in ECM synthesis, the collagen prolyl 4-hydroxylases (C-P4Hs), is induced specifically by hypoxia-inducible factor 1. Conclusion: Hypoxia inducibility of C-P4Hs ensures sufficient C-P4H activity in hypoxic chondrocytes. Significance: Quantitative regulation of C-P4H may be a key modality by which hypoxia influences early chondrocyte survival and differentiation. Hypoxia-inducible factors (HIFs) are the master regulators of hypoxia-responsive genes. They play a critical role in the survival, development, and differentiation of chondrocytes in the avascular hypoxic fetal growth plate, which is rich in extracellular matrix (ECM) and in its main component, collagens. Several genes involved in the synthesis, maintenance, and degradation of ECM are regulated by HIFs. Collagen prolyl 4-hydroxylases (C-P4Hs) are key enzymes in collagen synthesis because the resulting 4-hydroxyprolines are necessary for the stability of all collagen molecules. The vertebrate C-P4Hs are ␣ 2  2 tetramers with three isoforms of the catalytic ␣ subunit, yielding C-P4Hs of types I-III. C-P4H-I is the main form in most cells, but C-P4H-II is the major form in chondrocytes. We postulated here that post-translational modification of collagens, particularly 4-hydroxylation of proline residues, could be one of the modalities by which HIF regulates the adaptive responses of chondrocytes in fetal growth plates. To address this hypothesis, we used primary epiphyseal growth plate chondrocytes isolated from newborn mice with conditionally inactivated genes for HIF-1␣, HIF-2␣, or the von Hippel-Lindau protein. The data obtained showed that C-P4H ␣(I) and ␣(II) mRNA levels were increased in hypoxic chondrocytes in a manner dependent on HIF-1 but not on HIF-2. Furthermore, the increases in the C-P4H mRNA levels were associated with both increased amounts of the C-P4H tetramers and augmented C-P4H activity in hypoxia. The hypoxia inducibility of the C-P4H isoenzymes is thus likely to ensure sufficient C-P4H activity for collagen synthesis occurring in chondrocytes in a hypoxic environment.
An endoplasmic reticulum transmembrane prolyl 4-hydroxylase (P4H-TM) is able to hydroxylate the α... more An endoplasmic reticulum transmembrane prolyl 4-hydroxylase (P4H-TM) is able to hydroxylate the α subunit of the hypoxia-inducible factor (HIF) in vitro and in cultured cells, but nothing is known about its roles in mammalian erythropoiesis. We studied such roles here by administering a HIF-P4H inhibitor, FG-4497, to P4h-tm−/− mice. This caused larger increases in serum Epo concentration and kidney but not liver Hif-1α and Hif-2α protein and Epo mRNA levels than in wild-type mice, while the liver Hepcidin mRNA level was lower in the P4h-tm−/− mice than in the wild-type. Similar, but not identical, differences were also seen between FG-4497–treated Hif-p4h-2 hypomorphic (Hif-p4h-2gt/gt) and Hif-p4h-3−/− mice versus wild-type mice. FG-4497 administration increased hemoglobin and hematocrit values similarly in the P4h-tm−/− and wild-type mice, but caused higher increases in both values in the Hif-p4h-2gt/gt mice and in hematocrit value in the Hif-p4h-3−/− mice than in the wild-type. Hi...
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