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Y Naka

Publications and source records attributed to Y Naka.

At least 37 records · Page 2Linked to original sources
PubMed2000

cAMP pulse during preservation inhibits the late development of cardiac isograft and allograft vasculopathy.

The causes of transplant-associated coronary artery disease remain obscure, and there is no known treatment. Preservation injury of murine heterotopic vascularized cardiac isografts caused a small, albeit significant, increase in neointimal formation; preservation injury of allografts markedly increased both the incidence and severity of transplant-associated coronary artery disease. As cAMP is an important vascular homeostatic mediator the levels of which decline during organ preservation, buttressing cAMP levels solely during initial preservation both improved acute allograft function and reduced the severity of transplant-associated coronary artery disease in grafts examined 2 months later. Inhibiting the cAMP-dependent protein kinase abrogated these beneficial effects. cAMP treatment was associated with an early reduction in leukocyte infiltration and a reciprocal decrease in superoxide and increase in NO levels. These data indicate that alloantigen-independent injury to the graft, which occurs at the time of cardiac preservation, can set in motion pathological vascular events that are manifest months later. Furthermore, a cAMP pulse during cardiac preservation reduces the incidence and severity of transplant-associated coronary artery disease.

Animals↗
PubMed2000

Novel phenylpiperazine derivatives as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity.

Phenylpiperazine derivatives were synthesized as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity. Lead optimization led to compound 5k having the potent regulatory activity and demonstrating remarkable protective effects against the lethal challenge of LPS in mice. suggesting that 5k would be a promising drug candidate for the treatment of TNF-alpha associated diseases including septic shock.

Animals↗
PubMed2000

Novel DMARDs on the basis of a new concept of dual cytokine regulation, TNF-alpha suppression and IL-10 augmentation.

A series of arylpiperazine derivatives was synthesized to obtain agents showing apparent therapeutic effects in a chronic inflammatory animal model, starting from a lead possessing potent dual cytokine regulatory activity in vivo. We found a pyrimidylpiperazine derivative 17c showing the dual regulatory activity and an excellent therapeutic effect in an adjuvant-induced arthritis model.

Animals↗
PubMed2000

Antisense intercellular adhesion molecule-1 (ICAM-1) oligodeoxyribonucleotide delivered during organ preservation inhibits posttransplant ICAM-1 expression and reduces primary lung isograft failure.

Transiently increased expression of leukocyte adhesion receptors after lung preservation contributes to early graft demise by recruiting leukocytes, activating complement, and causing microcirculatory stasis. We hypothesized that inhibiting intercellular adhesion molecule-1 (ICAM-1) expression even briefly may significantly improve lung graft function and that the preservation period might provide a unique window to deliver a therapeutic pulse of antisense oligonucleotide ICAM-1 to inhibit ICAM-1 expression after transplantation. Interleukin-1beta-treated rat pulmonary endothelial cells given a 20-mer phosphorothioate oligonucleotide comprising an antisense span targeted to the 3'-untranslated region of rat ICAM-1 demonstrated an oligonucleotide dose-dependent reduction in ICAM-1 expression. Using a cationic liposomal carrier, this same antisense oligonucleotide (but not the sense control) instilled into the pulmonary vasculature at the time of preservation reduced subsequent graft ICAM-1 expression and graft leukostasis and markedly improved oxygenation, pulmonary blood flow, and graft survival. These experiments demonstrate that the preservation period presents a window during which to target an anti-ICAM-1 expression strategy to inhibit early adhesion receptor expression and improve functional outcome after lung transplantation.

Animals↗
PubMed2000

The long-term outcome of a surgical repair of sinus of valsalva aneurysm.

BACKGROUND: In order to clarify the long-term outcome after surgical repair of a sinus of Valsalva aneurysm, we retrospectively assessed the operative results for patients treated in our institute. METHODS: The subjects were 27 patients who had undergone an operation between 1958 and 1996. For associated aortic regurgitation (AR) aortic valve repair was performed in 13 patients, 12 of whom had a ventricular septal defect (VSD); and an aortic valve replacement was performed in 3 patients, 1 of whom had a VSD. RESULTS: Five of the 13 patients who had aortic valve repair needed aortic valve replacement because AR developed after a period of between 7 and 13 years; those cases were complicated by VSD. Another 2 patients with mild AR also complicated by VSD are currently under observation. CONCLUSIONS: Although the postoperative outcome of the aortic valve repairs was good, cases that were complicated by VSD plus associated AR tended to develop AR later after surgery. Therefore, careful observation of the postoperative course is necessary.

Adolescent↗
PubMed2000

Arginine vasopressin in the treatment of 50 patients with postcardiotomy vasodilatory shock.

BACKGROUND: The barroreflex-mediated secretion of arginine vasopressin has been found to be defective in a variety of vasodilatory shock states, such as postcardiotomy shock, and administration of the hormone markedly improves vasomotor tone and blood pressure. The high incidence of vasodilatory shock in patients undergoing left ventricular assist device (LVAD) implantation makes this population an ideal model in which to assess the risks and benefits of vasopressin. METHODS: The medical records of the 102 patients receiving LVADs at Columbia-Presbyterian Medical Center from January 1995 to August 1998 were reviewed. Fifty patients were eligible for study based on a history of arginine vasopressin administration in the operating room or intensive care unit within 24 hours of implantation. RESULTS: Despite LVAD implantation and the administration of vasopressors, patients were hypotensive with a mean arterial pressure less than 60 mm Hg. The administration of vasopressin (0.09+/-0.05 U/min) increased mean arterial pressure (58+/-13 to 75+/-14 mm Hg; p<0.001) while reducing norepinephrine administration (11.7+/-13 to 7.9+/-6.0 mcg/min; p = 0.023). There was no significant change in LVAD flow. The incidence of compromised regional perfusion was not different between LVAD patients who received vasopressin as compared to hemodynamically stable LVAD patients who did not receive vasopressin. CONCLUSIONS: We have demonstrated vasopressin at low doses to be a safe and an effective vasopressor in 50 patients with postcardiotomy vasodilatory shock.

Arginine Vasopressin↗
PubMed2000

Efficacy of mitral valve replacement for patients with mitral regurgitation and a dilated left ventricle.

Mitral regurgitation is a significant complication of end-stage cardiomyopathy, and its existence predicts poor survival. In general, it is thought that mitral valve replacement (MVR) alone is ineffective; however, there are few detailed reports of the clinical course of patients who have undergone MVR. Five patients with mitral regurgitation whose preoperative left ventricular end-systolic volume index was more than 100 ml/m2 were studied. Although their prognosis late after MVR became poor, none of them died within 30 days of the operation. Postoperative cardiac catheterization was performed 6.3+/-1.1 months after surgery; the end-diastolic volume had reduced (before: 193+/-26 ml/m2; after: 166+/-34 ml/m2, p<0.05), but the end-systolic volume had not (before: 110+/-7 ml/m2; after: 112+/-32 ml/m2). The end-systolic wall stress was substantially elevated preoperatively (238+/-29 kdyne/cm2) and tended to increase after surgery (295+/-96 kdyne/cm2). All the patients were able to return to work at some stage postoperatively (their New York Heart Association functional class improved to I or II), but 3 of the 5 patients died suddenly of heart failure at 3.3+/-1.6 years after surgery and the New York Heart Association functional class of the others worsened to III again. Mitral valve surgery, including MVR, can manage severe end-stage heart disease with mitral regurgitation.

Adult↗
PubMed1999

Identification of optimal conditions for lung graft storage with Euro-Collins solution by use of a rat orthotopic lung transplant model.

BACKGROUND: Lung preservation disrupts normal vascular homeostasis, resulting in increased permeability, vasoconstriction, and endothelial cell adhesion for neutrophils. We hypothesized that a storage strategy that best preserves post-lung transplantation (LTX) vascular homeostasis might be organ and species specific. Because of the potential utility of a rat LTX model for developing improved lung preservation strategies, we have attempted to identify the optimal physical conditions for rat lung graft storage. METHODS AND RESULTS: Conditions that were tested included harvest inflation pressure (0, 10, or 20 mm Hg), inflation gas composition (100% N(2), room air, or 100% O(2)), and storage temperature (4 degrees, 10 degrees, or 15 degrees C). Modified Euro-Collins solution served as the base preservation solution for all experiments, with a preservation duration of 4 to 6 hours. Arterial oxygenation (PaO(2), mm Hg), pulmonary vascular resistance (mm Hg/mL per minute), recipient survival (%), and graft neutrophil infiltration (DeltaAbs(460 nm)/min) were measured 30 minutes after transplantation of the left lung and exclusion of the right lung from the circulation. All tested conditions significantly affect post-LTX vascular homeostasis. Inflation at 10 mm Hg pressure preserved lungs significantly better than did other pressures. There was a tendency for room air to improve all measured variables compared with 100% N(2) or 100% O(2) and a significant improvement in recipient survival with room air storage. Of the 3 storage temperatures investigated, 10 degrees C storage provided the best preservation in terms of PaO(2), graft neutrophil infiltration, and survival. CONCLUSIONS: We conclude that storage at 10 degrees C, 10 mm Hg inflation pressure, with room air establishes optimal lung storage conditions with Euro-Collins solution in this rat LTX model. These data suggest that these conditions should be used to evaluate new and potentially improved preservation strategies.

Animals↗
PubMed1999

A Case of Adenoid Squamous Cell Carcinoma of the Breast Skin.

We report a case of a 45-year-old Japanese women with adenoid squamous cell carcinoma (ASCC) of the left breast skin. The patient had showed a large mass in the left breast region with axillary swelling about 1 year before admission. Grossly, the tumor was an extensively ulcerated and elevated lesion measuring 15 x 16 x 5cm. Based on the tumor biopsy and cytologic examination of the axillary lymph nodes, squamous cell carcinoma (SCC) was diagnosed. No evidence of distant metastasis was identified. A modified radical mastectomy with left axillary node dissection was performed. Microscopically, the resected tumor showed on invasive proliferation of atypical squamous cells with marked keratinization. At the periphery of the tumor, an adenoid growth pattern was frequently seen with a transitional area showing squamous cell carcinoma and adenoid growth components. ASCC was diagnosed. A transition between the overlying squamous cell epithelium and squamous cell carcinoma component was also seen, thus the tumor was thought to haveoriginated from the breast skin. The patient died of respiratory failure due tomultiple lung metastasis about 1 month after the mastectomy. Tumor rarely originates at the breast region to include both the mammary glands and breast skin. The pathogenesis and management of ASCC are discussed following the presentation of this case.

Journal Article↗
PubMed1999

Analysis of the elephant trunk method in patients with extensive thoracic aortic aneurysm.

We assessed the appropriate length of an elephant trunk prosthesis based on our experience with 9 patients experiencing extensive thoracic aneurysms. There were 3 patients with a true aneurysm, 5 patients with a dissecting aortic aneurysm, and 1 patient with a true plus dissecting aortic aneurysm. The subjects were 4 men and 5 women and, at the time of operation, were from 38 to 74 years old. The second-stage operations were performed on 6 patients from 9 days to 6 months after the first-stage operation. In the first-stage operation, one patient died of pneumonia during the hospital stay and another died of multi-organ infarction after 15 months. In the second-stage operation, two patients died of brain hemorrhage in the chronic stage after the operation. The length of the elephant trunk prosthesis was 3 cm in the three early patients, and in one of them the elephant trunk could not be utilized due to its insufficient length. In the next three patients, the length was extended to 5 cm, but one of patient experienced an expansion of the aneurysm in the descending aorta due to a graft of insufficient length which could not decompress the aneurysmal wall. Therefore, in the last three patients, the length was further extended to 10 cm, and the second-stage operation was performed uneventfully on the 64th, 9th and 45th day, respectively after the first-stage operation within a continuous hospital stay. Neither expansion of the aneurysm nor thromboembolism was found during the waiting period for any of the second-stage operations. Accordingly, we recommend using a 10 cm elephant trunk prosthesis.

Adult↗
PubMed1999

Superior protection in orthotopic rat lung transplantation with cyclic adenosine monophosphate and nitroglycerin-containing preservation solution.

BACKGROUND: Primary lung graft failure is common, and current lung preservation strategies are suboptimal. Because the decline in lung levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate during preservation could enhance adhesiveness of endothelial cells for leukocytes as well as increase vascular permeability and vasoconstriction, we hypothesized that buttressing these levels by means of a preservation solution would significantly improve lung preservation. METHODS: An orthotopic rat left lung transplantation model was used. Lungs were harvested from male Lewis rats and preserved for 6 hours at 4 degrees C with (1) Euro-Collins solution (n = 8); (2) University of Wisconsin solution (n = 8); (3) low-potassium dextran glucose solution (n = 8); (4) Columbia University solution (n = 8), which contains a cyclic adenosine monophosphate analog (dibutyryl cyclic adenosine monophosphate) and a nitric oxide donor (nitroglycerin) to buttress cyclic guanosine monophosphate levels; or (5) Columbia University solution without cyclic adenosine monophosphate or nitroglycerin (n = 8). PaO2, pulmonary vascular resistance, and recipient survival were evaluated 30 minutes after left lung transplantation and removal of the nontransplanted right lung from the pulmonary circulation. RESULTS: Among all groups studied, grafts stored with Columbia University solution demonstrated the highest Pa O2 (355 +/- 25 mm Hg for Columbia University solution versus 95 +/- 22 mm Hg for Euro-Collins solution, P <.01, 172 +/- 55 mm Hg for University of Wisconsin solution, P <.05, 76 +/- 15 mm Hg for low-potassium dextran glucose solution, P <.01, and 82 +/- 25 mm Hg for Columbia University solution without cyclic adenosine monophosphate or nitroglycerin, P <.01) and the lowest pulmonary vascular resistances (1 +/- 0.2 mm Hg * mL-1 * min-1 for Columbia University solution versus 12 +/- 4 mm Hg * mL-1 * min-1 for Euro-Collins solution, P <.01, 9 +/- 2 mm Hg * mL-1 * min-1 for University of Wisconsin solution, 14 +/- 6 mm Hg * mL-1 * min-1 for low-potassium dextran glucose solution, P <.01, and 8 +/- 2 mm Hg * mL-1 * min-1 for Columbia University solution without cyclic adenosine monophosphate and nitroglycerin). These functional and hemodynamic improvements provided by Columbia University solution were accompanied by decreased graft leukostasis and decreased recipient tumor necrosis factor alpha and interleukin 1alpha levels compared with the other groups. In toto, these improvements translated into superior survival among recipients of Columbia University solution-preserved grafts (100% for Columbia University solution, 37% for Euro-Collins solution, P <.01, 50% for University of Wisconsin solution, P <.05, 50% for low-potassium dextran glucose solution, P <.05, and 13% for Columbia University solution without cyclic adenosine monophosphate and nitroglycerin, P <.01). CONCLUSION: Nitroglycerin and cyclic adenosine monophosphate confer beneficial vascular effects that make Columbia University solution a superior lung preservation solution in a stringent rat lung transplantation model.

Adenosine↗
PubMed1999

Development of an off bypass mitral valve repair.

BACKGROUND: The Bow Tie Repair (BTR), a single edge-to-edge suture opposing the anterior and posterior leaflets of the mitral valve (MV), has led to satisfactory reduction of mitral regurgitation (MR) with few re-operations and excellent hemodynamic results. The simplicity of the repair lends itself to minimally invasive approaches. A MV grasper has been developed that will coapt both leaflets and fasten the structures with a graduated spiral screw. METHODS: Eleven explanted adult human MVs were mounted in a mock circulatory loop created for simulating a variety of hemodynamic conditions. The MV grasper was used to place a screw in each valve, which was then continuously run for 300,000 to 1,000,000 cycles with a fixed transvalvular pressure gradient. At the completion of these studies, the valves were stressed to a maximal transvalvular gradient for ten minutes. In seven cases, MR was induced and subsequently repaired using the MV screw. In vivo, the MV screw was tested in nine male canines. Through a subcostal incision, the MV grasper entered the left ventricle, approximated the mitral leaflets and deployed the MV screw under direct visualization via an atriotomy. Follow-up transthoracic echocardiograms were done at postoperative week 1, 6, and 12 to identify screw migration, MV regurgitation/stenosis or clot formation. Dogs were sacrificed up to postoperative week 12 to allow gross and histologic assessment. RESULTS: In vitro, no MV screw detached from the valve leaflets or migrated during the durability testing period of 6.8 million cycles, including periods of stress load testing up to 350 mm Hg. The percent regurgitant flow used to assess MR statistically decreased with the placement of the screw from 72 +/- 7% to 34 +/- 17%; p = 0.0025. In vivo, seven dogs whose valves were examined within the first 48 hours revealed leaflet coaptation with an intact MV screw and no evidence of MR. Two dogs, followed for a prolonged period, had serial postoperative echocardiograms demonstrating consistent coaptation, no screw migration, no clot, and no regurgitation or stenosis. In the animal sacrificed at 12 weeks, the MV screw was integrated into the tissue of both leaflets. CONCLUSIONS: The MV screw has provided durable leaflet coaptation and has reduced regurgitation in human MVs. Initial data on the MV screw's biocompatibility and interactions with living valve tissue is promising. Our early success supports further efforts towards the maturation of this prototype into off bypass mitral valve repair technology.

Animals↗
PubMed1998

Cardiac graft intercellular adhesion molecule-1 (ICAM-1) and interleukin-1 expression mediate primary isograft failure and induction of ICAM-1 in organs remote from the site of transplantation.

During the first few hours after heart transplantation, the occurrence of graft failure is unpredictable and devastating. An explosive cascade of inflammatory events within the reperfused graft vasculature is likely to be mediated, at least in part, by the local expression of the leukocyte adhesion receptor intercellular adhesion molecule-1 (ICAM-1, CD54). Furthermore, although proinflammatory cytokines such as interleukin-1 (IL-1) are known to autoinduce their own (and ICAM-1) expression in vitro, there are no data to identify their functional in vivo cross talk in the setting of isograft transplantation. To determine the role of ICAM-1 in primary graft failure, we used an isogeneic vascularized model of heterotopic cardiac transplantation. ICAM-1 mRNA and protein increased in grafts during the early posttransplant period and were predominantly localized in the endothelium. The functional significance of this was established using donor hearts obtained from either ICAM-1-deficient (ICAM-1 -/-) or control (ICAM-1 +/+) mice. ICAM-1 +/+ grafts exhibited increased neutrophil infiltration, reduced left ventricular compliance, and poorer survival than did ICAM-1 -/- grafts. Increased ICAM-1 expression was not limited to ICAM-1 +/+ grafts but also occurred in unmanipulated recipient organs located remote from the site of surgery (but only after transplantation of ICAM-1 +/+, not ICAM-1 -/-, cardiac grafts). This expression of ICAM-1 in remote organs appeared to be triggered by IL-1alpha released from the graft, because (1) in situ hybridization revealed increased IL-1 mRNA within cells of the reperfused graft, including myocytes and endothelial cells; (2) ICAM-1 expression in remote organs coincided with a significant increase in serum levels of IL-1alpha after transplantation of ICAM-1 +/+ grafts; both remote organ ICAM-1 expression and IL-1alpha levels were blunted by implantation of ICAM-1 -/- grafts; and (3) remote organ ICAM-1 expression and neutrophil infiltration and IL-1 levels could be blocked by the administration of an IL-1 receptor antagonist. These data demonstrate an apparent positive-feedback loop in which local ICAM-1 and IL-1 expression leads to a mutual amplification of each other's expression within the reperfused graft, promulgating inflammatory events that are likely to be an important cause of primary cardiac graft failure. Because IL-1 receptor blockade reduces the IL-1-mediated autoinduction of IL-1, reduces the expression of ICAM-1 in both the graft and remote organs, and improves graft survival, it may provide a new and effective strategy to prevent the occurrence of primary cardiac graft failure.

Animals↗
PubMed1998

Triglyceride metabolism in heterozygote of Watanabe heritable hyperlipidemic rabbit.

The present study was conducted in order to examine the role of low-density lipoprotein (LDL)-receptor activity in very-low-density lipoprotein (VLDL) triglyceride metabolism in vivo. Fructose-feeding (10% in drinking water) for 2 weeks resulted in elevated plasma triglyceride in heterozygote of Watanabe heritable hyperlipidemic (WHHL) rabbit (WHHLH) associated with suppressed fractional catabolic rate (FCR) of plasma triglyceride, whereas Japanese white (JW) rabbit with normal LDL receptor activity showed no remarkable change in plasma triglyceride turnover after fructose-feeding, suggesting an involvement of LDL receptor activity on triglyceride metabolism. Thereafter, in order to stimulate cellular LDL receptor activity, fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitor, was administered orally (1.52 +/- 0.26 mg/kg) to fructose-fed WHHLH. Significant suppression of triglyceride secretion rate (TGSR) was observed after treatment. However, since plasma triglyceride level was markedly suppressed, FCR of plasma triglyceride was significantly elevated by fluvastatin. Thus, it is speculated from the present data that LDL receptor activity is significantly involved in VLDL triglyceride metabolism in rabbits.

Animals↗
PubMed1997

Complement activation as a cause for primary graft failure in an isogeneic rat model of hypothermic lung preservation and transplantation.

Although agents that inhibit complement activation may be beneficial in discordant xenotransplantation, it is not known whether local complement activation occurs and is deleterious after isogeneic lung transplantation. Lungs were harvested from Lewis rats subjected to 4 degrees C 6-hr preservation followed by transplantation into strain-, gender-, and weight-matched recipients. Transplanted lungs demonstrated increased immunostaining for C5b-9 compared with nontransplanted controls, confirming local complement activation in this isograft model. To investigate the physiologic relevance of complement activation in the transplanted lung, the native pulmonary artery was ligated after transplantation, and pulmonary vascular resistance (mmHg/ml/min), arterial oxygenation (mmHg), graft neutrophil infiltration (myeloperoxidase activity, deltaAbs 460 nm/min), and recipient survival were measured at 30 min. Animals received either saline (control; n=22) or soluble complement receptor type-1 (sCR1, 15 mg/kg; n=19) 2 min before reperfusion. Animals treated with sCR1 showed a marked reduction in serum complement hemolytic activity (CH50; 90% lower than that of control animals, P<0.001). Compared with controls, sCR1-treated animals showed reduced pulmonary vascular resistance (2.9+/-1.1 vs. 8.5+/-1.5 mmHg/ml/min, P<0.05), improved arterial oxygenation (194+/-34 vs. 91+/-17 mmHg, P<0.05), decreased neutrophil infiltration (35% decrease, P<0.005), and improved recipient survival (74% vs. 23%, P<0.005). In parallel with the reduction in complement hemolytic activity in sCR1-treated animals, immunohistology of the transplanted lung revealed decreased C5b-9 deposition compared with controls. Taken together, these data indicate that complement activation occurs after lung preservation and transplantation in an isograft model, and that inhibiting complement activation improves outcome after transplantation.

Animals↗
PubMed1997

Effect of long-term exogenous hyperinsulinemia and fructose or glucose supplementation on triglyceride turnover in rats.

We examined the effect of long-term (6 months) hyperinsulinemia on VLDL-triglyceride turnover in male Wistar rats. Hyperinsulinemia was induced in rats by daily s.c. injection of Ultralente insulin (6 U/day at 19:00). Fructose (F) or glucose (G) was supplied in the drinking water (10%) in order to prevent hypoglycemia. The rats were divided into 5 groups: (1) hyperinsulinemia with F water: group F + I; (2) hyperinsulinemia with G water: group G + I; (3) F water alone: group F; (4) G water alone: group G; and (5) control rats without sugar water group C. After 6 months of daily insulin injection triglyceride secretion rate (TGSR) was estimated using Triton WR1339 in all the rats. Groups F + I and G + I were obese and hypoglycemic compared to the other groups. Fasting plasma glucose level of group F was higher than any other group value. TGSR of group F + I was significantly higher than that of the control group, while that of group G + I was not, indicating that long-term hyperinsulinemia can stimulate hepatic triglyceride production when the rats were supplemented only with fructose. On the other hand, the rats in group G + I showed the lowest plasma free fatty acid level of all and their postheparin lipolytic activity was significantly elevated compared to that of the control rats. Moreover, they had suppressed plasma triglyceride levels and its fractional catabolic rate was significantly increased, suggesting that hyperinsulinemia can still stimulate triglyceride removal from the circulation of glucose supplemented rats even at month 6. In conclusion, exogenous hyperinsulinemia can stimulate hepatic triglyceride secretion even after 6 months duration when supplemented with fructose, while its stimulating effect on triglyceride removal from the circulation can be seen only with glucose supplementation. Thus, the effect of long-term hyperinsulinemia on plasma triglyceride turnover differs depending on the supplemented monosaccharides.

Animals↗
PubMed1997

Nuclear factor interleukin 6 motifs mediate tissue-specific gene transcription in hypoxia.

Activation of transcription at the nuclear factor interleukin 6 (NF-IL-6) DNA binding motif modulates expression of multiple genes important in host adaptive and developmental mechanisms. Studies showing that hypoxia-induced transcription of IL-6 in cultured endothelial cells was due to transcriptional activation by the NF-IL-6 motif in the promoter (Yan, S.-F., Tritto, I., Pinsky, D., Liao, H., Huang, J., Fuller, G., Brett, J., May, L., and Stern, D. (1995) J. Biol. Chem. 270, 11463-11471) led us to prepare transgenic mice using 115- or 14-base pair regions of the promoter encompassing the NF-IL-6 site ligated to the lacZ reporter gene and the basal thymidine kinase promoter. On exposure to hypoxia or induction of ischemia, mice bearing either of the constructs showed prominent expression of the transgene in lung and cardiac vasculature and in the kidney but not in the liver (parenchyma or vasculature). In contrast, transgenic mice bearing a mutationally inactivated NF-IL-6 site showed no increase in transgene expression in hypoxia. Gel retardation assays revealed time-dependent, hypoxia-enhanced nuclear binding activity for the NF-IL-6 site in nuclear extracts of the heart, lung, and kidney but not in the liver; the hypoxia-enhanced band disappeared on addition of antibody to C/EBPbeta-NF-IL-6. Consistent with the specificity of hypoxia-mediated activation of C/EBPbeta-NF-IL-6, gel retardation assays showed no change in the intensity of the hypoxia-enhanced gel shift band in the presence of excess unlabeled oligonucleotide probes or antibodies related to other transcription factors, including NFkappaB, AP1, cAMP response element-binding protein, SP1, and hypoxia-inducible factor 1. These data indicate that the transcription factor NF-IL-6 is sensitive to environmental oxygen deprivation, and the tissue-specific pattern of gene expression suggests that local mechanisms have an important regulatory effect.

Animals↗