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1.
Kyobu Geka ; 76(9): 711-713, 2023 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-37735731

RESUMO

A 51 years-old male with sudden onset of chest and back pain was referred to our hospital from another hospital. Contrast-enhanced computed tomography( CT) revealed the presence of Stanford type A acute aortic dissection with critically narrow true lumen in the ascending aorta. Then, emergency surgery was performed. One umbilical tape tourniquet was placed around the ascending aorta. A vent tube was inserted into the main pulmonary artery. A venous drainage cannula was inserted into the right atrium. In the head-down position, pulmonary artery venting and venous drainage were initiated. As the blood puressure fell down around 40 mmHg, the ascending aorta was incised. A cannula (DLP 24 Fr) was placed in the true lumen and the aorta was snared. Cardiopulmonary bypass was established followed by selective antegrade cardioplegia, and systemic cooling. An entry was found in the ascending aorta, so ascending aorta graft replacement was performed under selective antegrade cerebral perfusion. There were no perioperative complications, and he was discharged home on 24th postoperative day. There is still remain controversies as to the optimal arterial cannulation site for cardiopulmonary bypass in patients with Stanford type A aortic dissection. We think the ascending aorta is most simply, rapidly and reliably available. In this case, direct true lumen cannulation in the ascending aorta was useful.


Assuntos
Aorta Torácica , Dissecção Aórtica , Humanos , Masculino , Pessoa de Meia-Idade , Aorta/diagnóstico por imagem , Aorta/cirurgia , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/cirurgia , Cânula , Cateterismo
2.
Kyobu Geka ; 76(8): 652-655, 2023 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-37500556

RESUMO

Metastatic cardiac tumors are known to be more common than primary cardiac tumors, and most patients are asymptomatic. In patients with renal cell carcinoma (RCC) with cardiac metastases, total tumor resection is known to improve the prognosis. We report a case of a successfully resected RCC with right atrial metastasis under cardiopulmonary bypass. A 71-year-old female with abdominal distention was diagnosed with right RCC and extension to the right atrium. After neoadjuvant chemotherapy, she underwent right nephrectomy and neiection of intraocular tumor extention with partial right atrium under cardiopulmonary bypass, because the tumor tightly adhered to the right atrium. She had a good postoperative course and was discharged home on the 22nd postoperative day. Nine months after surgery, she shows no sign of recurrence.


Assuntos
Fibrilação Atrial , Carcinoma de Células Renais , Neoplasias Cardíacas , Neoplasias Renais , Feminino , Humanos , Idoso , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/patologia , Fibrilação Atrial/cirurgia , Veia Cava Inferior/patologia , Veia Cava Inferior/cirurgia , Átrios do Coração/cirurgia , Neoplasias Cardíacas/diagnóstico por imagem , Neoplasias Cardíacas/cirurgia , Neoplasias Cardíacas/patologia , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Nefrectomia
3.
Kyobu Geka ; 76(5): 375-378, 2023 May.
Artigo em Japonês | MEDLINE | ID: mdl-37150918

RESUMO

A 78-year-old male with sudden onset of chest and back pain was transported to our institution by ambulance. Upon arrival at our hospital, he also complained of abdominal pain. Contrast-enhanced computed tomography (CT) revealed the presence of Stanford type A acute aortic dissection complicated with intestinal ischemia;because of the effects of aortic dissection, the superior mesenteric artery 378 Vol.76 No.5(2023-5) (SMA) was obstructed, leading to the complication of intestinal ischemia. An arterial blood gas test showed elevated lactate and metabolic acidosis. We immediately performed resection of the necrotic portion of the intestine and bypass of the common iliac artery to the SMA. Subsequently, after confirmation of the improvement of acidosis, ascending aortic replacement was performed on the same day. Although the patient's condition was complicated by acute kidney injury and pneumonia, he was discharged home on the 55th postoperative day. Acute aortic dissection complicated by intestinal ischemia has a poor prognosis;however, here we reported a life-saving surgical procedure in a patient with this presentation.


Assuntos
Dissecção Aórtica , Isquemia Mesentérica , Masculino , Humanos , Idoso , Artéria Mesentérica Superior , Dissecção Aórtica/complicações , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/cirurgia , Isquemia Mesentérica/diagnóstico por imagem , Isquemia Mesentérica/etiologia , Isquemia Mesentérica/cirurgia , Aorta Abdominal , Isquemia/etiologia , Isquemia/cirurgia
4.
Kyobu Geka ; 74(8): 620-622, 2021 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-34334606

RESUMO

A single coronary artery is a very rare anomaly and is usually asymptomatic. Here we report a case of a single coronary artery complicated with Stanford type A acute aortic dissection. A 58-year-old male with chest pain was transported to our institution by ambulance. He was diagnosed with a single coronary artery accompanied by acute coronary syndrome. The single coronary artery originated from the left sinus of Valsalva and the right coronary branch coursed between the aorta and the pulmonary artery. It was, therefore considered difficult to perform catheter intervention, and urgent coronary artery bypass surgery was planned. Enhanced computed tomography, however, revealed Stanford type A acute aortic dissection, and aortic root replacement combined with coronary artery bypass grafting was performed by emergency. The postoperative course was uneventful.


Assuntos
Dissecção Aórtica , Doença da Artéria Coronariana , Dissecção Aórtica/complicações , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/cirurgia , Aorta , Ponte de Artéria Coronária , Humanos , Masculino , Pessoa de Meia-Idade
5.
Kyobu Geka ; 74(7): 550-553, 2021 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-34193793

RESUMO

The patient was a 45-year-old man who was transported by ambulance to a nearby clinic owing to sudden chest pain. He was diagnosed with myocardial infarction and giant coronary artery aneurysm by coronary arteriogram and underwent an emergency intervention for the myocardial infarction. The patient was referred to our hospital. Intraoperative findings showed the mass-like right coronary artery aneurysm at the anterior to the right atrium. The origin of the right coronary artery was ligated in addition to the fenestration and the proximal and distal regions of the coronary artery aneurysm. It has been reported that coronary artery aneurysms are usually asymptomatic and are often discovered by chance during screenings, such as echocardiography, computed tomography, and coronary arteriogram. Here, we report a surgical case of giant right coronary artery aneurysm complicated by acute myocardial infarction.


Assuntos
Aneurisma Coronário , Infarto do Miocárdio , Aneurisma Coronário/complicações , Aneurisma Coronário/diagnóstico por imagem , Aneurisma Coronário/cirurgia , Angiografia Coronária , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/cirurgia , Ecocardiografia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações
6.
Clin Case Rep ; 8(8): 1357-1360, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32884753

RESUMO

The incidence of infective endocarditis (IE) due to S pneumoniae has decreased, thanks to antibiotics. However, when it does occur, it can be lethal. The present case provides a reminder of the potential lethality of this postoperative infection.

7.
J Artif Organs ; 23(4): 315-320, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32448955

RESUMO

Cardiopulmonary bypass-associated acute kidney injury may appear postoperatively, but predictive factors are unclear. We investigated the potential of regional tissue oxygen saturation as a predictor of cardiopulmonary bypass-associated acute kidney injury. We analyzed the clinical data of 150 adult patients not on dialysis who underwent elective cardiac surgical procedures during January 2015-March 2017. Near-infrared spectroscopy was used to measure regional oxygen saturation. Sensors were placed on the patients' forehead, abdomen, and thigh. The incidence of acute kidney injury was 2% at the end of surgery, 13% at 24 h, and 9% at 48 h, with the highest at 24 h after surgery. The multiple regression analysis revealed that the thigh regional oximetry during cardiopulmonary bypass, oxygen delivery index, and neutrophil count at the end of cardiopulmonary bypass and surgery were independent risk factors for acute kidney injury. The receiver-operating characteristic curve analysis suggested that a cutoff of regional oxygen saturation at the thigh of ≤ 67% was predictive of acute kidney injury within 24 h after surgery. In conclusion, the regional oxygen saturation at the thigh during cardiopulmonary bypass is a crucial marker to predict postoperative acute kidney injury in adults undergoing cardiac surgery.


Assuntos
Injúria Renal Aguda/etiologia , Ponte Cardiopulmonar/efeitos adversos , Oxigênio/análise , Coxa da Perna/irrigação sanguínea , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oximetria , Prognóstico , Estudos Prospectivos , Fatores de Risco , Espectroscopia de Luz Próxima ao Infravermelho/métodos
8.
Kyobu Geka ; 69(2): 152-5, 2016 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-27075159

RESUMO

It is reported that 20% of cardiac myxomas are located in the right atrium. An 81-year-old man presented with dyspnea, general fatigue and leg edema lasting for a year. Echocardiography revealed an 80 mm tumor occupying the right atrium and the right ventricle. At surgery, the tumor attached to the atrial septum was removed with the surrounding septal wall. As the tricuspid annulus was dilated, tricuspid annuloplasty with an artificial ring was also carried out. After coming off cardiopulmonary bypass, the patient developed pulmonary hypertension with the pulmonary arterial pressure being 80% of the systemic pressure, which subsided gradually day by day. Histopathological diagnosis was cardiac myxoma. Postoperative lung perfusion scintigraphy revealed postoperative multiple defects. It was considered that multiple tumor embolisms in the distal pulmonary artery caused postoperative pulmonary hypertension. Careful follow-up for remote recurrence would be essential.


Assuntos
Átrios do Coração/cirurgia , Mixoma/cirurgia , Embolia Pulmonar/cirurgia , Idoso de 80 Anos ou mais , Ecocardiografia , Humanos , Masculino , Mixoma/complicações , Mixoma/patologia , Embolia Pulmonar/complicações , Tomografia Computadorizada por Raios X
9.
Kyobu Geka ; 69(3): 197-200, 2016 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-27075285

RESUMO

According to the current guidelines for acute pulmonary embolism in Japan, it is standard to perform surgical thrombectomy only after introducing percutaneous cardiopulmonary support (PCPS) for circulatory collapse. We experienced 2 cases of surgical thrombectomy without using PCPS. The 1st patient was a 49-year-old man. Computed tomography (CT) on admission revealed a thrombus in the main trunk of the pulmonary artery. He developed severe dyspnea and drop of consciousness after admission, and underwent emergency surgical thrombectomy. The 2nd patient was a 52-year-old man whose levels of consciousness and arterial oxygenation rapidly declined after admission. His CT revealed thrombi in the main trunk of the pulmonary artery, and he underwent emergency thrombectomy. Both patients had a history of diabetes and obesity. At our institute, we actively choose surgical thrombectomy for cases in which a thrombus is revealed in the main trunk of the pulmonary artery on CT and for cases in which abnormal symptoms and/or signs such as impaired consciousness and oxygenation develop.


Assuntos
Embolia Pulmonar/cirurgia , Doença Aguda , Complicações do Diabetes , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Trombectomia/métodos
10.
Case Rep Med ; 2014: 279374, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25477969

RESUMO

A female patient in her 30s was referred to us with a mass approximately 8 centimeters in diameter in right lung segment 6. Bronchoscopy was done, and a tumorous lesion obstructing right B6 was found. Biopsy of this lesion supported suspicions of sarcoma or spindle cell carcinoma. Contrast-enhanced CT showed that the mass extended to and obstructed the right main pulmonary artery. A skip lesion was also suspected in the periphery of pulmonary artery trunk. The tumor was removed by right pneumonectomy accompanied by resection of the main and left pulmonary arteries under cardiopulmonary bypass. The pulmonary artery trunk and the left pulmonary artery were reconstructed with a vascular graft. Collectively, intimal sarcoma originating from the right main pulmonary artery with extension into the right lung was diagnosed. Significant extension of pulmonary artery sarcoma into the lung, as was observed in the present case, is considered to be rare, and to our knowledge this is the first report in which the primary lesion was biopsied by bronchoscopy.

11.
Worm ; 2(2): e23005, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24058870

RESUMO

The endoplasmic reticulum (ER) is the intracellular organelle responsible for the synthesis, folding and assembly of proteins destined for secretion and the endomembrane system of the cell. ER quality control (ERQC) is an intensively studied surveillance mechanism that selectively degrades misfolded proteins to ensure that only properly folded proteins exit the ER en route to the Golgi compartment. Proper protein folding is indispensable for the differentiation and function of cells that secrete high levels of protein and defects in protein folding are implicated in many pathologies, including metabolic, genetic, neurodegenerative and inflammatory diseases. Accumulation of misfolded proteins in the ER activates an adaptive set of signaling pathways, collectively known as the unfolded protein response (UPR), to resolve protein misfolding and restore ER homeostasis. Nonsense-mediated RNA decay (NMD) is an RNA surveillance system that selectively degrades nascent mRNAs containing premature termination codons (PTCs). Recently, we used a genetic screen to identify genes that interact with UPR signaling in C. elegans. These studies identified NMD-associated genes that are required for ER protein folding homeostasis. These findings link the quality control systems required for ER protein folding and RNA biogenesis, provide new insights into mechanisms of ERQC and have implications on diseases of ER dysfunction and therapeutic approaches based on NMD inhibition. Here, we discuss the biological significance of these findings and future directions for study.

12.
Proc Natl Acad Sci U S A ; 109(21): 8079-84, 2012 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-22562797

RESUMO

The unfolded protein response (UPR) is an intracellular stress-signaling pathway that counteracts the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Because defects in ER protein folding are associated with many pathological states, including metabolic, neurologic, genetic, and inflammatory diseases, it is important to understand how the UPR maintains ER protein-folding homeostasis. All metazoans have conserved the fundamental UPR transducers IRE1, ATF6, and PERK. In Caenorhabditis elegans, the UPR is required to prevent larval lethality and intestinal degeneration. Although ire-1-null worms are viable, they are particularly sensitive to ER stress. To identify genes that are required for development of ire-1-null worms, we performed a comprehensive RNA interference screen to find 10 genes that exhibit synthetic growth and intestinal defects with the ire-1(v33) mutant but not with atf-6(tm1153) or pek-1(ok275) mutants. The expression of two of these genes, exos-3 and F48E8.6, was induced by ER stress, and their knockdown in a wild-type strain caused ER stress. Because these genes encode subunits of the exosome complex that functions in mRNA surveillance, we analyzed other gene products required for nonsense-mediated mRNA decay (NMD). Our results demonstrate that defects in smg-1, smg-4, and smg-6 in C. elegans and SMG6 in mammalian cells cause ER stress and sensitize to the lethal effects of ER stress. Although ER stress did not activate mRNA surveillance complex assembly, ER stress did induce SMG6 expression, and NMD regulators were constitutively localized to the ER. Importantly, the findings demonstrate a unique and fundamental interaction where NMD-mediated mRNA quality control is required to prevent ER stress.


Assuntos
Caenorhabditis elegans/genética , Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/fisiologia , Homeostase/fisiologia , RNA/genética , Resposta a Proteínas não Dobradas/genética , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/fisiologia , Linhagem Celular Transformada , Sobrevivência Celular/fisiologia , Códon sem Sentido/genética , Células HeLa , Hepatócitos/citologia , Humanos , Larva/fisiologia , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Deficiências na Proteostase/genética , Deficiências na Proteostase/metabolismo , Interferência de RNA/fisiologia , Proteínas de Ligação a RNA , Telomerase/genética , Telomerase/metabolismo , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
13.
Mol Biol Cell ; 23(9): 1728-41, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22419820

RESUMO

A disintegrin-like and metalloprotease with thrombospondin type I motif (ADAMTS9) is a member of the secreted metalloprotease family that is believed to digest extracellular matrix (ECM) proteins outside of cells. Its Caenorhabditis elegans orthologue, GON-1, is involved in ECM degradation and is required for gonad morphogenesis. ADAMTS9 and GON-1 have similar domain structures, and both have a unique C-terminal domain called the "GON domain," whose function remains unknown. Here we show that down-regulation of human ADAMTS9 and C. elegans GON-1 results in the inhibition of protein transport from the endoplasmic reticulum (ER) to the Golgi. This phenotype was rescued by the expression of the GON domain localizing in the ER in human cells and C. elegans. We propose a novel function of ADAMTS9 and GON-1 in the ER that promotes protein transport from the ER to the Golgi. This function is GON-domain dependent but protease activity independent.


Assuntos
Proteínas ADAM/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Metaloendopeptidases/metabolismo , Proteínas ADAM/genética , Proteína ADAMTS9 , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Linhagem Celular , Sequência Conservada , Células HEK293 , Humanos , Metaloendopeptidases/genética , Transporte Proteico
14.
Autophagy ; 4(6): 841-3, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18670192

RESUMO

The endoplasmic reticulum (ER) is the primary site for folding and quality control for proteins destined to the cell surface and intracellular organelles. A variety of cellular insults alter ER homeostasis to disrupt protein folding, cause the accumulation of misfolded proteins, and activate an autophagic response. However, the molecular signaling pathways required for ER stress-induced autophagy are largely unknown. Recently, we discovered that a novel-type protein kinase C family member (PKCtheta) is required for ER stress-induced autophagy. We show that ER stress, in a Ca(2+)-dependent manner, induces PKCtheta phosphorylation within the activation loop and localization with LC3-II in punctate cytoplasmic structures. Pharmacological inhibition, siRNA-mediated knockdown, or transdominant-negative mutant expression of PKCtheta block the ER stress-induced autophagic response. PKCtheta activation is not required for autophagy induced by amino acid starvation, and PKCtheta activation in response to ER stress does not require either the mTOR kinase or the unfolded protein response signaling pathways. Herein, we review and discuss the significance of these findings with respect to regulation of autophagy in response to ER stress.


Assuntos
Autofagia/fisiologia , Retículo Endoplasmático/metabolismo , Isoenzimas/metabolismo , Estresse Oxidativo , Proteína Quinase C/metabolismo , Animais , Ativação Enzimática , Proteína Quinase C-theta
15.
J Biol Chem ; 283(22): 15370-80, 2008 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-18356160

RESUMO

Autophagy is an evolutionally conserved process for the bulk degradation of cytoplasmic proteins and organelles. Recent observations indicate that autophagy is induced in response to cellular insults that result in the accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER). However, the signaling mechanisms that activate autophagy under these conditions are not understood. Here, we report that ER stress-induced autophagy requires the activation of protein kinase C (PKC), a member of the novel-type PKC family. Induction of ER stress by treatment with either thapsigargin or tunicamycin activated autophagy in immortalized hepatocytes as monitored by the conversion LC3-I to LC3-II, clustering of LC3 into dot-like cytoplasmic structures, and electron microscopic detection of autophagosomes. Pharmacological inhibition of PKC or small interfering RNA-mediated knockdown of PKC prevented the autophagic response to ER stress. Treatment with ER stressors induced PKC phosphorylation within the activation loop and localization of phospho-PKC to LC3-containing dot structures in the cytoplasm. However, signaling through the known unfolded protein response sensors was not required for PKC activation. PKC activation and stress-induced autophagy were blocked by chelation of intracellular Ca(2+) with BAPTA-AM. PKC was not activated or required for autophagy in response to amino acid starvation. These observations indicate that Ca(2+)-dependent PKC activation is specifically required for autophagy in response to ER stress but not in response to amino acid starvation.


Assuntos
Antibacterianos/farmacologia , Autofagia/efeitos dos fármacos , Retículo Endoplasmático/enzimologia , Inibidores Enzimáticos/farmacologia , Hepatócitos/enzimologia , Isoenzimas/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tapsigargina/farmacologia , Tunicamicina/farmacologia , Animais , Cálcio/metabolismo , Linhagem Celular , Estruturas da Membrana Celular/metabolismo , Quelantes/farmacologia , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Retículo Endoplasmático/ultraestrutura , Ativação Enzimática/efeitos dos fármacos , Lactosilceramidas/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Dobramento de Proteína , Proteína Quinase C-theta
16.
J Cell Sci ; 119(Pt 11): 2342-53, 2006 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-16723740

RESUMO

Mammalian Delta9 stearoyl-CoA desaturase 1 (SCD1) is a key enzyme in the biosynthesis of mono-unsaturated fatty acids in the endoplasmic reticulum (ER). It is a short-lived multispanning ER membrane protein, reported to be degraded by the ubiquitin-proteasome-independent pathway. We have examined SCD1 protein degradation using cultured mammalian cells. Exogenously expressed SCD1 in CHO-K1 cells was localized to the ER and turned over with a half-life of approximately 3 hours. Unexpectedly, proteasome inhibitors increased the half-life of SCD1 to approximately 6 hours. Endogenously expressed SCD1 in adipocyte-differentiated NIH 3T3-L1 cells was also rapidly degraded in a proteasome inhibitor-sensitive manner. In the presence of proteasome inhibitors, polyubiquitylated SCD1 accumulated in the ER and interacted with AAA-ATPase p97, which is involved in ER-associated degradation (ERAD). The 66-residue N-terminal segment carrying the PEST sequence is mainly responsible for SCD1 degradation and this segment induced instability in an otherwise stable ER membrane protein. Furthermore, SCD1 was degraded constitutively irrespective of the cellular levels of unsaturated fatty acids, which strictly regulate SCD1 gene expression. These findings indicate that the ubiquitin-proteasome-dependent ERAD system is also involved in constitutive SCD1 degradation.


Assuntos
Retículo Endoplasmático/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Ubiquitina/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Células CHO , Linhagem Celular , Células Cultivadas , Cricetinae , Retículo Endoplasmático/enzimologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Isoenzimas/biossíntese , Isoenzimas/efeitos dos fármacos , Isoenzimas/metabolismo , Leupeptinas/farmacologia , Camundongos , Células NIH 3T3 , Proteínas Nucleares/metabolismo , Estearoil-CoA Dessaturase/efeitos dos fármacos , Estearoil-CoA Dessaturase/genética
17.
Cell ; 124(3): 587-99, 2006 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-16469704

RESUMO

Regulated intramembrane proteolysis (RIP) of endoplasmic reticulum (ER) membrane-anchored transcription factors is known to maintain sterol homeostasis and to mediate the unfolded protein response (UPR). Here, we identified CREBH as a RIP-regulated liver-specific transcription factor that is cleaved upon ER stress and required to activate expression of acute phase response (APR) genes. Proinflammatory cytokines increase expression of ER membrane-anchored CREBH. In response to ER stress, CREBH is cleaved by site-1 and site-2 proteases to liberate an amino-terminal fragment that transits to the nucleus to activate transcription of the genes encoding serum amyloid P-component (SAP) and C-reactive protein (CRP). Proinflammatory cytokines and lipopolysaccharide activate the UPR and induce cleavage of CREBH in the liver in vivo. Together, our studies delineate a molecular mechanism for activation of an ER-localized transcription factor, CREBH, and reveal an unprecedented link by which ER stress initiates an acute inflammatory response.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Retículo Endoplasmático/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação/genética , Proteína C-Reativa/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/química , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Citocinas/metabolismo , DNA/genética , DNA/metabolismo , Feminino , Feto/metabolismo , Mediadores da Inflamação/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Gravidez , Pró-Proteína Convertases/metabolismo , Interferência de RNA , Serina Endopeptidases/metabolismo , Componente Amiloide P Sérico/metabolismo
18.
PLoS Genet ; 1(3): e37, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16184190

RESUMO

The unfolded protein response (UPR) is an adaptive signaling pathway utilized to sense and alleviate the stress of protein folding in the endoplasmic reticulum (ER). In mammals, the UPR is mediated through three proximal sensors PERK/PEK, IRE1, and ATF6. PERK/PEK is a protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 to inhibit protein synthesis. Activation of IRE1 induces splicing of XBP1 mRNA to produce a potent transcription factor. ATF6 is a transmembrane transcription factor that is activated by cleavage upon ER stress. We show that in Caenorhabditis elegans, deletion of either ire-1 or xbp-1 is synthetically lethal with deletion of either atf-6 or pek-1, both producing a developmental arrest at larval stage 2. Therefore, in C. elegans, atf-6 acts synergistically with pek-1 to complement the developmental requirement for ire-1 and xbp-1. Microarray analysis identified inducible UPR (i-UPR) genes, as well as numerous constitutive UPR (c-UPR) genes that require the ER stress transducers during normal development. Although ire-1 and xbp-1 together regulate transcription of most i-UPR genes, they are each required for expression of nonoverlapping sets of c-UPR genes, suggesting that they have distinct functions. Intriguingly, C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis. In contrast, pek-1 is required for induction of approximately 23% of i-UPR genes but is dispensable for the c-UPR. As pek-1 and atf-6 mainly act through sets of nonoverlapping targets that are different from ire-1 and xbp-1 targets, at least two coordinated responses are required to alleviate ER stress by distinct mechanisms. Finally, our array study identified the liver-specific transcription factor CREBh as a novel UPR gene conserved during metazoan evolution.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Regulação da Expressão Gênica , Fator 6 Ativador da Transcrição/genética , Animais , Proteínas de Caenorhabditis elegans/química , Proteínas de Ciclo Celular/genética , Retículo Endoplasmático/genética , Retículo Endoplasmático/fisiologia , MAP Quinase Quinase 1/genética , Desnaturação Proteica , Transcrição Gênica
19.
J Biochem ; 134(3): 373-84, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14561723

RESUMO

The genome-wide expression pattern of budding yeast Saccharomyces cerevisiae in response to mild heat treatment in a non-fermentable carbon source was analyzed using DNA microarrays. Of 5,870 open reading frames (nuclear genome transcripts) examined, 104 genes were upregulated and 287 genes were downregulated upon shifting of the cells from 25 degrees C to 37 degrees C. Forty upregulated genes and 235 downregulated genes encoded localization-assigned proteins. Of 113 heat-repressible genes (excluding 122 heat-repressible ribosomal genes), 36 were mitochondria-related genes, whereas only 2 of 40 heat-inducible genes were mitochondria-related. In particular, 9 genes involved in the mitochondrial respiratory chain and 7 genes involved in mitochondrial protein translocation were significantly repressed, suggesting that mitochondrial respiratory function and biogenesis were downregulated. Consistent with these findings, the growth of yeast cells in a non-fermentable carbon source was repressed at 37 degrees C and the mitochondria isolated from heat-stressed cells exhibited compromised preprotein-import activity compared with those from unstressed cells. In contrast, many genes involved in glycolysis and the metabolic pathway to produce glutamate via the tricarboxylic acid cycle, which is essential for biosynthetic reactions, were upregulated. Yeast cells might downregulate mitochondrial function to circumvent heat-induced oxidative stress, upregulate stress-related genes, and remodel genes for metabolic pathways in response to mild heat stress: an adaptive response at the expense of cell growth.


Assuntos
Mitocôndrias/fisiologia , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Regulação para Baixo , Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Transtornos de Estresse por Calor , Mitocôndrias/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Temperatura , Regulação para Cima
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