Cellular Carbonyl Stress Enhances the Expression of Plasminogen Activator Inhibitor-1 in Rat White Adipocytes via Reactive Oxygen Species-dependent Pathway

Carbonyl stress is one of the important mechanisms of tissue damage in vascular complications of diabetes. In the present study, we observed that the plasminogen activator inhibitor-1 (PAI-1) levels in serum and its gene expression in adipose tissue were up-regulated in aged OLETF rats, model animals of obese type 2 diabetes. To study the mechanism of PAI-1 up-regulation, we examined the effect of advanced glycation end products (AGEs) and the product of lipid peroxidation (4-hydroxy-2-nonenal (HNE)), both of which are endogenously generated under carbonyl stress. Stimulation of primary white adipocytes by either AGE or HNE resulted in the elevation of PAI-1 in culture medium and at mRNA levels. The up-regulation of PAI-1 was also observed by incubating the cells in high glucose medium (30 mm, 48 h). The stimulatory effects by AGE or high glucose were inhibited by antioxidant, pyrrolidine dithiocarbamate, and reactive oxygen scavenger, probucol, suggesting a pivotal role of oxidative stress in white adipocytes. We also found that the effect by HNE was inhibited by antioxidant, N-acetylcysteine and that a specific inhibitor of glutathione biosynthesis, l-buthionine-S,R-sulfoximine, augmented the effect of subthreshold effect of HNE. Bioimaging of reactive oxygen species (ROS) by a fluorescent indicator, 6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate, revealed ROS production in white adipocytes treated with AGE or HNE. These results suggest that cellular carbonyl stress induced by AGEs or HNE may stimulate PAI-1 synthesis in and release from adipose tissues through ROS formation. Carbonyl stress is one of the important mechanisms of tissue damage in vascular complications of diabetes. In the present study, we observed that the plasminogen activator inhibitor-1 (PAI-1) levels in serum and its gene expression in adipose tissue were up-regulated in aged OLETF rats, model animals of obese type 2 diabetes. To study the mechanism of PAI-1 up-regulation, we examined the effect of advanced glycation end products (AGEs) and the product of lipid peroxidation (4-hydroxy-2-nonenal (HNE)), both of which are endogenously generated under carbonyl stress. Stimulation of primary white adipocytes by either AGE or HNE resulted in the elevation of PAI-1 in culture medium and at mRNA levels. The up-regulation of PAI-1 was also observed by incubating the cells in high glucose medium (30 mm, 48 h). The stimulatory effects by AGE or high glucose were inhibited by antioxidant, pyrrolidine dithiocarbamate, and reactive oxygen scavenger, probucol, suggesting a pivotal role of oxidative stress in white adipocytes. We also found that the effect by HNE was inhibited by antioxidant, N-acetylcysteine and that a specific inhibitor of glutathione biosynthesis, l-buthionine-S,R-sulfoximine, augmented the effect of subthreshold effect of HNE. Bioimaging of reactive oxygen species (ROS) by a fluorescent indicator, 6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate, revealed ROS production in white adipocytes treated with AGE or HNE. These results suggest that cellular carbonyl stress induced by AGEs or HNE may stimulate PAI-1 synthesis in and release from adipose tissues through ROS formation. Adipose tissue directly secretes biologically active molecules (adipocytokines) including plasminogen activator inhibitor-1 (PAI-1) 1The abbreviations used are: PAI-1plasminogen activator inhibitor-1ROSreactive oxygen speciesRCSreactive carbonyl speciesAGEadvanced glycation end productHNE4-hydroxy-2-nonenal8-OHdG8-hydroxy-2′-deoxyguanosineBSAbovine serum albuminPDTCpyrrolidinedithiocarbamateNACN-acetylcysteineBSOl-buthionine-S,R-sulfoximinePBSphosphate-buffered salineELISAenzyme-linked immunosorbent assayDCF-DA6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate. and actively affects other tissues. This is thought to be one of the risk factors for the development of obesity-linked disorders (1Spiegelman B.M. Choy L. Hotamisligil G.S. Graves R.A. Tontonoz P. J. Biol. Chem. 1993; 268: 6823-6826Abstract Full Text PDF PubMed Google Scholar). High plasma PAI-1 activity, which regulates fibrinolytic as well as thrombotic processes, is a frequent finding in obesity (2Vague P. Juhan-Vague I. Chabert V. Alessi M.C. Atlan C. Metabolism. 1989; 38: 913-915Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 3Landin K. Stigendal L. Eriksson E. Krotkiewski M. Risberg B. Tengborn L. Smith U. Metabolism. 1990; 39: 1044-1048Abstract Full Text PDF PubMed Scopus (301) Google Scholar, 4Eriksson P. Reynisdottir S. Lönnqvist F. Stemme V. Hamsten A. Arner P. Diabetologia. 1998; 41: 65-71Crossref PubMed Scopus (229) Google Scholar) and/or in Type II (non-insulin-dependent) diabetes (5Auwerx J. Bouillon R. Collen D. Geboers J. Arteriosclerosis. 1988; 8: 68-72Crossref PubMed Google Scholar, 6Potter van Loon B.J. Kluft C. Radder J.K. Blankenstein M.A. Meinders A.E. Metabolism. 1993; 42: 945-949Abstract Full Text PDF PubMed Scopus (217) Google Scholar, 7McGill J.B. Schneider D.J. Arfken C.L. Lucore C.L. Sobel B.E. Diabetes. 1994; 43: 104-109Crossref PubMed Scopus (0) Google Scholar). Among the studies about PAI-1 expression in adipose tissue, biological significances of visceral fat during the development of obesity have been highlighted (8Shimomura I. Funahashi T. Takahashi M. Maeda K. Kotani K. Nakamura T. Yamashita S. Miura M. Fukuda Y. Takemura K. Tokunaga K. Matsuzawa Y. Nat. Med. 1996; 2: 800-803Crossref PubMed Scopus (819) Google Scholar). Furthermore, Alessi et al. (9Alessi M.C. Peiretti F. Morange P. Henry H. Nalbone G. JuhanVague I. Diabetes. 1997; 46: 860-867Crossref PubMed Scopus (0) Google Scholar) demonstrated that human adipocytes in culture produce PAI-1 and that omental fat produces more PAI-1 than subcutaneous adipose tissue in obese or non-obese individuals. However, the mechanism leading to up-regulation of PAI-1 has not been clearly elucidated. plasminogen activator inhibitor-1 reactive oxygen species reactive carbonyl species advanced glycation end product 4-hydroxy-2-nonenal 8-hydroxy-2′-deoxyguanosine bovine serum albumin pyrrolidinedithiocarbamate N-acetylcysteine l-buthionine-S,R-sulfoximine phosphate-buffered saline enzyme-linked immunosorbent assay 6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate. The pathological conditions of diabetes with obesity have been widely associated with reactive oxygen species (ROS) and reactive carbonyl species (RCS), which may be key intermediates leading to diabetic complications. RCS originates from a multitude of mechanistically related pathways, like glycation (10Thornalley P.J. Langborg A. Minhas H.S. Biochem. J. 1999; 344: 109-116Crossref PubMed Scopus (1011) Google Scholar) and lipid peroxidation (11Fu M-X. Requena J.R. Jenkins A.J. Lyons T.J. Baynes J.W. Thorpe S.R. J. Biol. Chem. 1996; 271: 9982-9986Abstract Full Text Full Text PDF PubMed Scopus (722) Google Scholar). Glycation, a spontaneous amino-carbonyl reaction between reducing sugars and proteins, is a major source of RCS production. The complex reaction sequence is initiated by the reversible formation of a Schiff base, which undergoes an Amadori rearrangement to form a relatively stable ketoamine product during early glycation. A series of further reactions involving sugar fragmentation and formation of α-dicarbonyl compound yield stable advanced glycation end products (AGEs) under chronic hyperglycemia (12Vlassara H. Ann. Med. 1996; 28: 419-426Crossref PubMed Scopus (188) Google Scholar, 13Singh R. Barden A. Mori T. Beilin L. Diabetologia. 2001; 44: 129-146Crossref PubMed Scopus (1970) Google Scholar). Carbonyl stress also leads to the intracellular formation of 4-hydroxy-2-nonenal (HNE), one of the active end products of lipid peroxidation. Interestingly, RCS and AGEs can exert their detrimental cellular effects by increasing ROS production (14Lander H.M. Tauras J M. Ogiste J.S. Hori O. Moss R.A. Schmidt A.M. J. Biol. Chem. 1997; 272: 17810-17814Abstract Full Text Full Text PDF PubMed Scopus (679) Google Scholar), thereby forming a vicious cycle of ROS and RCS production. In the present study, to investigate the mechanisms underlying increased PAI-1 levels in obese diabetic conditions, we performed both in vivo and in vitro studies. For in vivo studies, gene expression and secretion of PAI-1 were measured in visceral adipose tissue using OLETF (Otsuka Long-Evans Tokushima fatty) rats, model animals of obese type II diabetes (15Kawano K. Hirashima T. Mori S. Saitoh Y. Kurosumi M. Natori T. Diabetes. 1992; 41: 1422-1428Crossref PubMed Scopus (0) Google Scholar). In parallel with the progression of diabetes, serum levels of both AGE and malondialdehyde derived from lipid peroxidation were shown to increase (16Nakamura S. Makita Z. Ishikawa S. Yasumura K. Fujii W. Yanagisawa K. Kawata T. Koike T. Diabetes. 1997; 46: 895-899Crossref PubMed Google Scholar, 17Tsuji T. Mizushige K. Noma T Murakami K. Ohmori K. Miyatake A. Kohno M. J. Cardiovasc. Pharmacol. 2001; 38: 868-874Crossref PubMed Scopus (66) Google Scholar). For in vitro studies, we examined the effects of AGE and HNE on the PAI-1 activity and its gene expression in rat white adipocytes differentiated in vitro. We focused on the role of carbonyl stress in the upregulation of PAI-1 expression. Animals—Male OLETF rats, model animals of Type II diabetes mellitus established in 1990 at Tokushima Research Institute (Otsuka Pharmaceutical Co., Ltd.) (15Kawano K. Hirashima T. Mori S. Saitoh Y. Kurosumi M. Natori T. Diabetes. 1992; 41: 1422-1428Crossref PubMed Scopus (0) Google Scholar), were generously supplied at 4 weeks of age. Male LETO (Long-Evans Tokushima Otsuka) rats served as normal controls. These animals were kept in an air-conditioned room (23 ± 2 °C, 55 ± 5% humidity) lighted 14 h a day (06:00 to 20:00) and were maintained on a standard diet and water ad libitum. These rats were sacrificed at 12, 20, 30, and 50 weeks of age, and blood was collected for determination of the plasma PAI-1 and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Immediately after decapitation, visceral fat was dissected out and frozen in liquid nitrogen and stored in a deep freezer (–80 °C) until use. At 29 weeks of age, OLETF and LETO rats were divided into four groups, which were injected with probucol (3, 10, or 30 mg/kg subcutaneously) or vehicle for fat cells were from fat of the tissue was in a type II for at with the tissue were through a into The were on for at 30 to the white fat cells and lipid to on the of the The was collected and through a to The cells was by a for at and in the culture The cells were in and in medium with bovine 4 4 50 and 50 The cells were at under an of 5% in and on after At the cells were to be differentiated to white adipocytes. at the of and and as a at the of and were to the The cells were to or for 12, and as pyrrolidinedithiocarbamate and 50 probucol were to the culture medium h to the of the HNE with at the of 10, 30, and were to the The cells were to HNE for and a of and l-buthionine-S,R-sulfoximine a were to the cells for h at the of and and 10, and of were by incubating 50 with in phosphate-buffered saline mm, at for 4 weeks as T. H. M. Y. U. S. A. 1992; PubMed Scopus Google Scholar, C. H. J. D. H. J. Med. 1989; PubMed Scopus Google Scholar) with a was under the conditions as controls. sugar was by The of and was measured by the of et al. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of PAI-1 in and levels were by of active PAI-1 in the culture medium as of the medium was with of medium with of bovine or HNE was at of or or 10, 30, or In or 50 a glutathione or or a inhibitor or was to the culture medium h or h to the of For the high glucose the cells were in 30 glucose for 48 the h of the medium was with of medium 30 glucose with of bovine In the cells were in 30 glucose in with or 50 for 48 PAI-1 of the culture medium were using a rat PAI-1 and were as of active PAI-1 from white of of the cells were as The cells were with phosphate-buffered saline and from with into of phosphate-buffered saline and were for with the were measured by the of et al. J. Biol. Chem. Full Text PDF PubMed Google Scholar). PAI-1 levels in the serum were using the we used on the and activity of PAI-1 are of in were at for and the was used for determination of by a Institute for of of PAI-1 mRNA by was from visceral adipose tissue or white fat cells by using and of were by on by The were in for 30 at and with rat PAI-1 for h at the of with were as an for the of PAI-1 mRNA levels and were on using The levels of PAI-1 mRNA were as after with levels. ROS intracellular 6-carboxy-2′,7′-dichlorodihydrofluorescein was into cells and is by intracellular to This is in cells and can be to fluorescent by intracellular The cells on day of culture were to or 30 HNE for with of was for cells for 30 cells were with of for h or of for cells were examined under an fluorescent with an and for of the fluorescent were with a and stored in a of by white adipocytes on day were to of AGE for or 30 of HNE for and were with phosphate-buffered and with was treated with for at The were on The was on a and with for the were with a or and with or as a were by using and by of the to The of was using of PAI-1 in Adipose from OLETF examined the serum levels of and its gene expression in adipose tissue from OLETF The serum PAI-1 levels in OLETF rats to increase at the of weeks and a at the of 50 in LETO rats The PAI-1 mRNA levels in visceral fat of OLETF rats, not in LETO rats, increased in parallel with the progression of serum PAI-1 The serum glucose levels of OLETF rats at the of 12, 20, 30, and 50 weeks were ± ± ± and ± were in of LETO rats ± ± ± and ± we that OLETF rats spontaneous and hyperglycemia after the of weeks as (15Kawano K. Hirashima T. Mori S. Saitoh Y. Kurosumi M. Natori T. Diabetes. 1992; 41: 1422-1428Crossref PubMed Scopus (0) Google Scholar), which we found well with the increased expression of PAI-1 in visceral between PAI-1 and between the serum PAI-1 and the serum levels is in In OLETF rats, a was observed between the serum PAI-1 and the levels In was between in LETO rats serum PAI-1 be associated with oxidative stress during the development of diabetes in OLETF we examined the effect of probucol, a antioxidant, on PAI-1 activity, its gene and serum At the of 30 the increased levels of serum and adipose tissue PAI-1 mRNA in OLETF rats were by injected probucol in a However, in LETO rats, was increase in either serum PAI-1 or which was not by expression of PAI-1 mRNA in visceral fat was observed in LETO rats and of PAI-1 in by up-regulation of PAI-1 was observed in in vivo studies using OLETF rats, we performed in vitro studies by directly the effect of AGEs on PAI-1 expression in white fat cells in primary increased PAI-1 activity in culture medium from white adipocytes differentiated in shown in white adipocytes on to for h a increase in PAI-1 with a elevation at of and studies that cells treated with a increase in PAI-1 in the by and the of PAI-1 was The PAI-1 in cells during h of was as high as that in To or not the of PAI-1 secretion PAI-1 mRNA expression was by induced a increase in PAI-1 mRNA in white adipocytes adipocytes to of a increase in PAI-1 mRNA of and High in PAI-1 by and further the of oxidative stress in the up-regulation of PAI-1 expression by shown in AGE PAI-1 expression at both and mRNA which be inhibited by either or probucol oxygen to effect of AGE can be observed also by the cells were in high glucose for 48 glucose induced an increase in PAI-1 activity and gene expression with the cells in medium This by high glucose was also inhibited by or probucol of increase in PAI-1 expression by and reactive oxygen The cells on were with 30 glucose or glucose for 48 or 50 probucol was to the the h of the medium was with of medium 30 glucose and or probucol with of bovine PAI-1 in culture were measured by and from cells were to effects of and probucol on increase in PAI-1 The are the ± from or effects of and probucol on increase in PAI-1 The are the ± from or four by in PAI-1 in by up-regulation of PAI-1 expression was observed in white adipocytes in to we to the of lipid HNE can up-regulation of The effect of an increasing of HNE on PAI-1 expression was A and HNE at of 30 and increased PAI-1 expression h after studies that cells a increase in PAI-1 in the by and the of PAI-1 was The of HNE (30 increased the of PAI-1 during h of as high as cells The PAI-1 mRNA levels to increase 4 h after the of HNE and a at h of in PAI-1 by and of of HNE on PAI-1 by a shown in the in PAI-1 activity and PAI-1 mRNA by 30 HNE were inhibited by the other at of a glutathione synthesis l-buthionine-S,R-sulfoximine, which intracellular to augmented the effect of subthreshold of HNE on PAI-1 expression of the effect of HNE in PAI-1 activity and its gene expression by a glutathione synthesis The cells on were treated with 30 HNE or for at of 10, and was to the culture for PAI-1 in culture were measured by and the from cells were to effects of on PAI-1 The are the ± from or effects of on PAI-1 The are the ± from four by or ROS in the of the production from white adipocytes was using a fluorescent indicator, The fluorescent are shown in and with for h 30 after the of was observed in The increase in the of white adipocytes by was inhibited by the stimulatory of AGE was by HNE. 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