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1
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Vrzalova A, Vrzal R. Orchestra of ligand-activated transcription factors in the molecular symphony of SERPINE 1 / PAI-1 gene regulation. Biochimie 2025; 228:138-157. [PMID: 39321911 DOI: 10.1016/j.biochi.2024.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 09/04/2024] [Accepted: 09/20/2024] [Indexed: 09/27/2024]
Abstract
Plasminogen activator inhibitor 1 (PAI-1) is a crucial serine protease inhibitor that prevents plasminogen activation by inhibiting tissue- and urokinase-type plasminogen activators (tPA, uPA). PAI-1 is well-known for its role in modulating hemocoagulation or extracellular matrix formation by inhibiting plasmin or matrix metalloproteinases, respectively. PAI-1 is induced by pro-inflammatory cytokines across various tissues, yet its regulation by ligand-activated transcription factors is partly disregarded. Therefore, we have attempted to summarize the current knowledge on the transcriptional regulation of PAI-1 expression by the most relevant xenobiotic and endocrine receptors implicated in modulating PAI-1 levels. This review aims to contribute to the understanding of the specific, often tissue-dependent regulation of PAI-1 and provide insights into the modulation of PAI-1 levels beyond its direct inhibition.
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Affiliation(s)
- Aneta Vrzalova
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic
| | - Radim Vrzal
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic.
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2
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Baker LA, Minor KM, Tate N, Furrow E. Whole blood gene expression analysis of spontaneous hypertriglyceridemia in dogs suggests an underlying pro-thrombotic process. PLoS One 2024; 19:e0313343. [PMID: 39531449 PMCID: PMC11556679 DOI: 10.1371/journal.pone.0313343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Hypertriglyceridemia (HTG) is influenced by multiple genetic and environmental factors. Spontaneous, idiopathic HTG is common in the Miniature Schnauzer dog and presumed to have a strong genetic influence in this breed. To define genes that are differentially expressed in dogs with HTG, we performed RNA sequencing on peripheral blood of 13 Miniature Schnauzers with HTG and 18 controls. We identified 110 differentially expressed genes (DEGs). Pathway analysis suggests an ongoing pro-thrombotic, endothelial activation process in dogs with HTG. The gene with the largest fold change (5.4 ± 1.4, Padj = 4.4E-04), SERPINE1, encodes plasminogen activator inhibitor 1 (PAI-1), a known risk factor for atherosclerosis and thrombosis. Other top DEGs, including SHANK3, MMRN1, and FZD7, are involved in endothelial activation. Two of the top DEGs, ARHGAP29 and ARHGAP21, inhibit pro-thrombotic pathways and are potentially protective of disease sequelae. Top DEGs, including SERPINE1 and ARHGAP21, have also been linked to metabolic syndrome or its features (e.g. insulin resistance) in humans and animal models. Our findings indicate that HTG in the Miniature Schnauzer dog has similar features to HTG and metabolic syndrome in humans, highlighting the potential use of the dog as a spontaneous model for further research into the etiology and effects of HTG.
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Affiliation(s)
- Lauren A. Baker
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Katie M. Minor
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Nicole Tate
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Eva Furrow
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America
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Młynarska E, Hajdys J, Czarnik W, Fularski P, Leszto K, Majchrowicz G, Lisińska W, Rysz J, Franczyk B. The Role of Antioxidants in the Therapy of Cardiovascular Diseases-A Literature Review. Nutrients 2024; 16:2587. [PMID: 39203723 PMCID: PMC11357572 DOI: 10.3390/nu16162587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/24/2024] [Accepted: 07/30/2024] [Indexed: 09/03/2024] Open
Abstract
Antioxidants are endogenous and exogenous substances with the ability to inhibit oxidation processes by interacting with reactive oxygen species (ROS). ROS, in turn, are small, highly reactive substances capable of oxidizing a wide range of molecules in the human body, including nucleic acids, proteins, lipids, carbohydrates, and even small inorganic compounds. The overproduction of ROS leads to oxidative stress, which constitutes a significant factor contributing to the development of disease, not only markedly diminishing the quality of life but also representing the most common cause of death in developed countries, namely, cardiovascular disease (CVD). The aim of this review is to demonstrate the effect of selected antioxidants, such as coenzyme Q10 (CoQ10), flavonoids, carotenoids, and resveratrol, as well as to introduce new antioxidant therapies utilizing miRNA and nanoparticles, in reducing the incidence and progression of CVD. In addition, new antioxidant therapies in the context of the aforementioned diseases will be considered. This review emphasizes the pleiotropic effects and benefits stemming from the presence of the mentioned substances in the organism, leading to an overall reduction in cardiovascular risk, including coronary heart disease, dyslipidaemia, hypertension, atherosclerosis, and myocardial hypertrophy.
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Affiliation(s)
- Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (J.H.); (W.C.); (P.F.); (K.L.); (G.M.); (W.L.)
| | - Joanna Hajdys
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (J.H.); (W.C.); (P.F.); (K.L.); (G.M.); (W.L.)
| | - Witold Czarnik
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (J.H.); (W.C.); (P.F.); (K.L.); (G.M.); (W.L.)
| | - Piotr Fularski
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (J.H.); (W.C.); (P.F.); (K.L.); (G.M.); (W.L.)
| | - Klaudia Leszto
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (J.H.); (W.C.); (P.F.); (K.L.); (G.M.); (W.L.)
| | - Gabriela Majchrowicz
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (J.H.); (W.C.); (P.F.); (K.L.); (G.M.); (W.L.)
| | - Wiktoria Lisińska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (J.H.); (W.C.); (P.F.); (K.L.); (G.M.); (W.L.)
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland;
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland; (J.H.); (W.C.); (P.F.); (K.L.); (G.M.); (W.L.)
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4
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Huang C, AlSubki L, Yamaya A, Sung N, Kwak-Kim J. Poor ovarian response in assisted reproductive technology cycles is associated with anti-ovarian antibody and pro-inflammatory immune responses. J Reprod Immunol 2023; 160:104152. [PMID: 37778094 DOI: 10.1016/j.jri.2023.104152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 08/27/2023] [Accepted: 09/11/2023] [Indexed: 10/03/2023]
Abstract
Anti-ovarian antibody (AOA) could be considered an independent marker for autoimmune ovarian disease and predicting future premature ovarian failure (POF). This study aims to investigate if AOA is associated with poor ovarian response (POR) and pro-inflammatory immune responses in women undergoing assisted reproductive technology (ART) cycles. Two hundred forty-eight women undergoing ART cycles were divided into four groups based on AOA test results and the presence of POR: POR(-)/AOA(-) group (N = 148), POR(+)/AOA(-) group (N = 34), POR (-)/AOA(+) group (N = 44), POR(+)/AOA(+) group (N = 22). The POR patients have a significantly higher prevalence of AOA than non-POR patients (P < 0.05). Peripheral blood CD56 + natural killer (NK) cell level (%), NK cytotoxicity, CD19 +CD5 + B-1 cell level (%), and IFN-γ/IL-10 producing T helper (Th) 1/Th2 cell ratios were significantly higher in POR(+)/AOA(+) group than those of other groups (P < 0.001, P < 0.005, P < 0.01, P < 0.05, respectively). TNF-α/IL-10 producing Th1/Th2 cell ratio of POR(+)/AOA(+) group was significantly higher than those of POR(+)/AOA(-) and POR(-)/AOA(-) groups (P < 0.05, respectively). Homocysteine and vitamin D levels of the POR(+)/AOA(+) group were significantly lower than those of other groups (P < 0.005, respectively). Plasminogen activator inhibiter-1 (PAI-1) level of POR(+)/AOA(+) group was significantly higher than that of POR(-)/AOA(-) group (P < 0.05). In the POR(+)/AOA(+) group, the prevalence of antiphospholipid antibodies was significantly higher than that of the POR(+)/AOA(-) group (P = 0.005). Women with autoimmune POR (POR(+)/AOA(+)) have dysregulated pro-inflammatory immune responses and metabolic factors. The diagnostic and therapeutic approaches for autoimmune POR should be differentiated from those for non-autoimmune POR.
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Affiliation(s)
- Changsheng Huang
- Reproductive Medicine and Immunology, Obstetrics and Gynecology, Clinical Sciences Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Vernons Hill, IL 60061, USA; Department of Traditional Chinese Medicine and Rheumatology, Huazhong University of Science and Technology Union Shenzhen Hospital, The 6th Affiliated Hospital of Shenzhen University Medical School, Shenzhen, China
| | - Lujain AlSubki
- Reproductive Medicine and Immunology, Obstetrics and Gynecology, Clinical Sciences Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Vernons Hill, IL 60061, USA; Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia
| | - Ayano Yamaya
- Reproductive Medicine and Immunology, Obstetrics and Gynecology, Clinical Sciences Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Vernons Hill, IL 60061, USA; Department of Obstetrics and Gynecology, Hyogo Medical University, School of Medicine, Nishinomiya, Hyogo, Japan
| | - Nayoung Sung
- Reproductive Medicine and Immunology, Obstetrics and Gynecology, Clinical Sciences Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Vernons Hill, IL 60061, USA
| | - Joanne Kwak-Kim
- Reproductive Medicine and Immunology, Obstetrics and Gynecology, Clinical Sciences Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Vernons Hill, IL 60061, USA.
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Ohkura N, Morimoto-Kamata R, Kamikubo Y, Takahashi Y, Oishi K. Hypofibrinolytic phenotype in Tsumura Suzuki Obese Diabetes (TSOD) mice unrelated to hyperglycemia. Drug Discov Ther 2023; 17:346-350. [PMID: 37839864 DOI: 10.5582/ddt.2023.01064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2023]
Abstract
Obesity and diabetes mellitus are associated with increased risk of arterial thrombosis and venous thromboembolism. Tsumura Suzuki Obese Diabetes (TSOD) mice are useful models for elucidating the molecular mechanisms of these diseases. We investigated normoglycemic [Ng]-TSOD mice with a metabolic abnormality that was accompanied by a coagulative and fibrinolytic state with a phenotype that distinctly differed from that of standard TSOD mice. As in TSOD mice, plasminogen activation inhibitor-1 (PAI-1) that inhibits fibrinolysis was substantially augmented in Ng-TSOD mice, suggesting that they are hypofibrinolytic. However, blood clotting parameters were within the normal range in Ng-TSOD mice. These findings indicated that Ng-TSOD mice are novel models with a hypofibrinolytic phenotype that is not associated with hyperglycemia.
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Affiliation(s)
- Naoki Ohkura
- Laboratory of Host Defence, School of Pharma-Sciences, Teikyo University, Tokyo, Japan
| | - Riyo Morimoto-Kamata
- Laboratory of Host Defence, School of Pharma-Sciences, Teikyo University, Tokyo, Japan
| | - Yuichi Kamikubo
- Thrombo Translational Research Lab Inc., Kumamoto University Cooperation Incubator, Minami-Kumamoto, Kumamoto, Japan
| | - Yoshihisa Takahashi
- Department of Pathology, School of Medicine, International University of Health and Welfare, Narita, Japan
| | - Katsutaka Oishi
- Healthy Food Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan
- Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
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Stenberg K, Novotny GW, Lutz TA, Mandrup-Poulsen T, Bjørnvad CR. Obesity-induced changes in gene expression in feline adipose and skeletal muscle tissue. J Anim Physiol Anim Nutr (Berl) 2023; 107:1262-1278. [PMID: 36591865 DOI: 10.1111/jpn.13802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 11/14/2022] [Accepted: 12/05/2022] [Indexed: 01/03/2023]
Abstract
Indoor-confined cats are prone to developing obesity due to a sedentary life and an energy intake exceeding energy requirements. As in humans, feline obesity decreases insulin sensitivity and increases the risk of developing feline diabetes mellitus, but the pathophysiological mechanisms are currently poorly understood. Human obesity-related metabolic alterations seem to relate to changes in the expression of genes involved in glucose metabolism, insulin action and inflammation. The objective of the current study was to investigate changes in the expression of genes relating to obesity, glucose metabolism and inflammation in cats with non-experimentally induced obesity. Biopsies from the sartorius muscle and subcutaneous adipose tissue were obtained from 73 healthy, neutered, indoor-confined domestic shorthaired cats ranging from lean to obese. Quantification of obesity-related gene expression levels relative to glyceraldehyde-3-phosphate dehydrogenase was performed by quantitative real-time polymerase chain reaction. A negative association between obesity and adiponectin expression was observed in the adipose tissue (mean ± SD; normal weight, 27.30 × 10-3 ± 77.14 × 10-3 ; overweight, 2.89 × 10-3 ± 0.38 × 10-3 and obese, 2.93 × 10-3 ± 4.20 × 10-3 , p < 0.05). In muscle, the expression of peroxisome proliferative activated receptor-γ2 and plasminogen activator inhibitor-1 was increased in the obese compared to the normal-weight cats, and resistin was increased in the normal-weight compared to the overweight cats. There were no detectable obesity-related changes in the messenger RNA levels of inflammatory cytokines. In conclusion, a possible obesity-related low-grade inflammation caused by increased expression of key proinflammatory regulators was not observed. This could imply that the development of feline obesity and ensuing insulin resistance may not be based on tissue-derived inflammation, but caused by several determining factors, many of which still need further investigation.
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Affiliation(s)
- Kathrine Stenberg
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Guy W Novotny
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Departments of Hematology/Pathology, Herlev Hospital, Herlev, Denmark
| | - Thomas A Lutz
- Institute of Veterinary Physiology, Vetsuisse-Faculty University of Zurich, Zurich, Switzerland
| | | | - Charlotte Reinhard Bjørnvad
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
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7
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Rose M, Filiatreault A, Williams A, Guénette J, Thomson EM. Modulation of insulin signaling pathway genes by ozone inhalation and the role of glucocorticoids: A multi-tissue analysis. Toxicol Appl Pharmacol 2023; 469:116526. [PMID: 37088303 DOI: 10.1016/j.taap.2023.116526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/06/2023] [Accepted: 04/14/2023] [Indexed: 04/25/2023]
Abstract
Air pollution is associated with increased risk of metabolic diseases including type 2 diabetes, of which dysregulation of the insulin-signaling pathway is a feature. While studies suggest pollutant exposure alters insulin signaling in certain tissues, there is a lack of comparison across multiple tissues needed for a holistic assessment of metabolic effects, and underlying mechanisms remain unclear. Air pollution increases plasma levels of glucocorticoids, systemic regulators of metabolic function. The objectives of this study were to 1) determine effects of ozone on insulin-signaling genes in major metabolic tissues, and 2) elucidate the role of glucocorticoids. Male Fischer-344 rats were treated with metyrapone, a glucocorticoid synthesis inhibitor, and exposed to 0.8 ppm ozone or clean air for 4 h, with tissue collected immediately or 24 h post exposure. Ozone inhalation resulted in distinct mRNA profiles in the liver, brown adipose, white adipose and skeletal muscle tissues, including effects on insulin-signaling cascade genes (Pik3r1, Irs1, Irs2) and targets involved in glucose metabolism (Hk2, Pgk1, Slc2a1), cell survival (Bcl2l1), and genes associated with diabetes and obesity (Serpine1, Retn, Lep). lucocorticoid-dependent regulation was observed in the liver and brown and white adipose tissues, while effects in skeletal muscle were largely unaffected by metyrapone treatment. Gene expression changes were accompanied by altered phosphorylation states of insulin-signaling proteins (BAD, GSK, IR-β, IRS-1) in the liver. The results show that systemic effects of ozone inhalation include tissue-specific regulation of insulin-signaling pathway genes via both glucocorticoid-dependent and independent mechanisms, providing insight into mechanisms underlying adverse effects of pollutants.
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Affiliation(s)
- Mercedes Rose
- Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa K1A 0K9, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa K1H 8M5, Canada
| | - Alain Filiatreault
- Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa K1A 0K9, Canada
| | - Andrew Williams
- Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa K1A 0K9, Canada
| | - Josée Guénette
- Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa K1A 0K9, Canada
| | - Errol M Thomson
- Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa K1A 0K9, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa K1H 8M5, Canada.
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Harwansh RK, Yadav P, Deshmukh R. Current Insight into Novel Delivery Approaches of Resveratrol for Improving Therapeutic Efficacy and Bioavailability with its Clinical Updates. Curr Pharm Des 2023; 29:2921-2939. [PMID: 38053352 DOI: 10.2174/0113816128282713231129094715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 10/22/2023] [Accepted: 11/02/2023] [Indexed: 12/07/2023]
Abstract
Resveratrol (RSV) is a polyphenolic phytoalexin, and belongs to the stilbene family. RSV has several therapeutic activities such as cardioprotective, anticancer, and antioxidant. Apart from its therapeutic benefits, its pharmacological uses are limited due to low solubility, poor bioavailability, and short biological halflife. A researcher continuously focuses on overcoming the limitations of RSV through nanotechnology platforms to get the optimum health benefits. In this context, nanocarriers are pioneering to overcome these drawbacks. Nanocarriers possess high drug loading capacity, thermal stability, low production cost, longer shelflife, etc. Fortunately, scientists were proficient in delivering resveratrol-based nanocarriers in the present scenario. Nanocarriers can deliver drugs to the target sites without compromising the bioavailability. Thus, this review highlights how the latest nanocarrier systems overcome the shortcomings of RSV, which will be good for improving therapeutic efficacy and bioavailability. Moreover, recent updates on resveratrol-based novel formulations and their clinical trials have been addressed to manage several health-related problems.
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Affiliation(s)
- Ranjit K Harwansh
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, India
| | - Paras Yadav
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, India
| | - Rohitas Deshmukh
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, India
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Reifsnyder PC, Flurkey K, Doty R, Calcutt NA, Koza RA, Harrison DE. Rapamycin/metformin co-treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice. Aging Cell 2022; 21:e13666. [PMID: 35986566 PMCID: PMC9470898 DOI: 10.1111/acel.13666] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/09/2022] [Accepted: 06/23/2022] [Indexed: 02/01/2023] Open
Abstract
Rapamycin treatment has positive and negative effects on progression of type 2 diabetes (T2D) in a recombinant inbred polygenic mouse model, male NONcNZO10/LtJ (NcZ10). Here, we show that combination treatment with metformin ameliorates negative effects of rapamycin while maintaining its benefits. From 12 to 30 weeks of age, NcZ10 males were fed a control diet or diets supplemented with rapamycin, metformin, or a combination of both. Rapamycin alone reduced weight gain, adiposity, HOMA-IR, and inflammation, and prevented hyperinsulinemia and pre-steatotic hepatic lipidosis, but exacerbated hyperglycemia, hypertriglyceridemia, and pancreatic islet degranulation. Metformin alone reduced hyperinsulinemia and circulating c-reactive protein, but exacerbated nephropathy. Combination treatment retained the benefits of both while preventing many of the deleterious effects. Importantly, the combination treatment reversed effects of rapamycin on markers of hepatic insulin resistance and normalized systemic insulin sensitivity in this inherently insulin-resistant model. In adipose tissue, rapamycin attenuated the expression of genes associated with adipose tissue expansion (Mest, Gpam), inflammation (Itgam, Itgax, Hmox1, Lbp), and cell senescence (Serpine1). In liver, the addition of metformin counteracted rapamycin-induced alterations of G6pc, Ppara, and Ldlr expressions that promote hyperglycemia and hypertriglyceridemia. Both rapamycin and metformin treatment reduced hepatic Fasn expression, potentially preventing lipidosis. These results delineate a state of "insulin signaling restriction" that withdraws endocrine support for further adipogenesis, progression of the metabolic syndrome, and the development of its comorbidities. Our results are relevant for the treatment of T2D, the optimization of current rapamycin-based treatments for posttransplant rejection and various cancers, and for the development of treatments for healthy aging.
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Affiliation(s)
| | | | | | - Nigel A. Calcutt
- Department of PathologyUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Robert A. Koza
- Center for Molecular MedicineMaine Medical Center Research InstituteScarboroughMaineUSA
- Graduate School of Biomedical Sciences and EngineeringUniversity of MaineOronoMaineUSA
- Pennington Biomedical Research CenterBaton RougeLouisianaUSA
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Speelman T, Dale L, Louw A, Verhoog NJD. The Association of Acute Phase Proteins in Stress and Inflammation-Induced T2D. Cells 2022; 11:2163. [PMID: 35883605 PMCID: PMC9321356 DOI: 10.3390/cells11142163] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/02/2022] [Accepted: 07/04/2022] [Indexed: 02/06/2023] Open
Abstract
Acute phase proteins (APPs), such as plasminogen activator inhibitor-1 (PAI-1), serum amyloid A (SAA), and C-reactive protein (CRP), are elevated in type-2 diabetes (T2D) and are routinely used as biomarkers for this disease. These APPs are regulated by the peripheral mediators of stress (i.e., endogenous glucocorticoids (GCs)) and inflammation (i.e., pro-inflammatory cytokines), with both implicated in the development of insulin resistance, the main risk factor for the development of T2D. In this review we propose that APPs, PAI-1, SAA, and CRP, could be the causative rather than only a correlative link between the physiological elements of risk (stress and inflammation) and the development of insulin resistance.
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Affiliation(s)
| | | | | | - Nicolette J. D. Verhoog
- Biochemistry Department, Stellenbosch University, Van der Byl Street, Stellenbosch 7200, South Africa; (T.S.); (L.D.); (A.L.)
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11
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Jo A, Choi TG, Han JY, Tabor MH, Kolliputi N, Lockey RF, Cho SH. Age-Related Increase of Collagen/Fibrin Deposition and High PAI-1 Production in Human Nasal Polyps. Front Pharmacol 2022; 13:845324. [PMID: 35712705 PMCID: PMC9193225 DOI: 10.3389/fphar.2022.845324] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 05/12/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: Our previous studies showed an age-related increased prevalence of nasal polyps (NP) and reduced production of S100A8/9 in elderly patients with chronic rhinosinusitis with NP (CRSwNP). In this study, we investigated an unbiased age-related gene expression profile in CRSwNP subjects and healthy controls, and further identified the differences in their tissue remodeling. Methods: Microarrays using NP and uncinate tissues from health controls (elderly, age ≥65 vs. non-elderly, age 18-49) were performed, and differentially regulated genes were analyzed. Quantitative real-time PCR (qPCR), Immunostaining, Periodic acid-Schiff (PAS), trichrome staining, Western blot, and ELISA were performed for further investigation. Results: Microarrays identified differentially expressed genes according to disease and age; 278 in NP vs. controls, 75 in non-elderly NP vs. non-elderly controls, and 32 in elderly NP vs. elderly controls. qPCR confirmed that the PLAT gene was downregulated and the SERPINB2 gene upregulated in NP vs. controls. The serous glandular cell-derived antimicrobial protein/peptide-related genes such as BPIFB3, BPIFB2, LPO, and MUC7 were remarkably reduced in NP, regardless of age. SERPINE1 gene (plasminogen activator inhibitor-1, PAI-1) expression was significantly increased in elderly NP versus elderly controls. IHC and western blot confirmed significantly decreased production of MUC7 and LPO in NP versus controls. There was a trend of age-related reduction of submucosal gland cells in normal controls. Trichrome and immunofluorescence staining demonstrated an age-related increase of collagen and fibrin deposition in NP, consistent with increased PAI-1 production. Conclusion: This study demonstrated age-related differential glandular remodeling patterns and fibrosis in NP and normal controls. PAI-1 expression was significantly increased in elderly NP versus elderly controls, suggesting PAI-1 as a potential treatment target in elderly NP.
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Affiliation(s)
- Ara Jo
- Division of Allergy-Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Tae Gyu Choi
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, South Korea
| | - Jung Yeon Han
- Division of Allergy-Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Mark H. Tabor
- Department of Otolaryngology-Head and Neck Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Narasaiah Kolliputi
- Division of Allergy-Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Richard F. Lockey
- Division of Allergy-Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Seong H. Cho
- Division of Allergy-Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Division of Allergy-Immunology, James A. Haley Veterans’ Hospital, Tampa, FL, United States
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12
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Correlation of Vitamin D3, PAI-1, and HCG Hormone in Pre- and Post-Menopausal in Babylon Province. Rep Biochem Mol Biol 2022; 11:36-43. [PMID: 35765537 PMCID: PMC9208565 DOI: 10.52547/rbmb.11.1.36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 11/29/2021] [Indexed: 01/11/2023]
Abstract
Background Menopause is a unique event in women's life it usually occurs naturally, most often after age 50 when woman has not menstruated in 12 consecutive months. This study was planned to assess the relationship between Vitamin D3 level, PAI-1 and HCG in Babylon women at age <50 years as pre-menopausal and> 50 years as post-menopausal. Methods The sample were selected from a group of pre- and post-menopausal women, 30 and 50 respectively. All the tests were evaluated to measure Vitamin D3 level, PAI-1 and HCG level. The sample was collected between July 2019 and January 2020 at Merjan medical city GIT and Liver Center, Babylon province, Iraq. Results The result of current study revealed that there are significant differences in vitamin D3 level in various age categories within postmenopausal women (p= 0.02) also there is no significant differences in PAI-1 and HCG with in these two groups, p= 0.08 and 0.07, respectively. Also, there is significant negative correlation between vitamin D3 and PAI-1 in postmenopausal women (p. value is 0.01). Conclusion Indeed, postmenopausal women regarded as elderly, but they have sufficient vitamin D3 and normal PAI-I levels as markers for normal non fibrosis status.
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13
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Gaggini M, Ndreu R, Michelucci E, Rocchiccioli S, Vassalle C. Ceramides as Mediators of Oxidative Stress and Inflammation in Cardiometabolic Disease. Int J Mol Sci 2022; 23:ijms23052719. [PMID: 35269861 PMCID: PMC8911014 DOI: 10.3390/ijms23052719] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/24/2022] [Accepted: 02/26/2022] [Indexed: 12/13/2022] Open
Abstract
Ceramides, composed of a sphingosine and a fatty acid, are bioactive lipid molecules involved in many key cellular pathways (e.g., apoptosis, oxidative stress and inflammation). There is much evidence on the relationship between ceramide species and cardiometabolic disease, especially in relationship with the onset and development of diabetes and acute and chronic coronary artery disease. This review reports available evidence on ceramide structure and generation, and discusses their role in cardiometabolic disease, as well as current translational chances and difficulties for ceramide application in the cardiometabolic clinical settings.
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Affiliation(s)
- Melania Gaggini
- Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124 Pisa, Italy; (M.G.); (R.N.); (E.M.); (S.R.)
| | - Rudina Ndreu
- Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124 Pisa, Italy; (M.G.); (R.N.); (E.M.); (S.R.)
| | - Elena Michelucci
- Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124 Pisa, Italy; (M.G.); (R.N.); (E.M.); (S.R.)
| | - Silvia Rocchiccioli
- Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124 Pisa, Italy; (M.G.); (R.N.); (E.M.); (S.R.)
| | - Cristina Vassalle
- Fondazione CNR-Regione Toscana G Monasterio, 56124 Pisa, Italy
- Correspondence: ; Tel.: +39-050-3153525
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14
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Clément AA, Lacaille M, Lounis MA, Biertho LD, Richard D, Lemieux I, Bergeron J, Mounier C, Joanisse DR, Mauriège P. Intra-abdominal adipose depot variation in adipogenesis, lipogenesis, angiogenesis, and fibrosis gene expression and relationships with insulin resistance and inflammation in premenopausal women with severe obesity. J Physiol Biochem 2022; 78:527-542. [PMID: 35000091 DOI: 10.1007/s13105-021-00855-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/21/2021] [Indexed: 10/19/2022]
Abstract
Although severe obesity is associated with insulin resistance (IR) and inflammation, secretory function of intra-abdominal adipose tissues and their relationships with IR and inflammation markers remain poorly understood. Aims were to measure gene expression of adipogenic (C/EBPα/β, PPARγ-1/2, SREBP-1c, LXRα), lipogenic (SCD1, DGAT-1/2), angiogenic (VEGFα, leptin), and fibrotic (LOX, COL6A3) factors in the round ligament (RL), omental (OM), and mesenteric (ME) fat depots and to evaluate their relationships with IR and inflammation markers in 48 women with severe obesity undergoing bariatric surgery. Gene expression was assessed by RT-qPCR, and plasma glucose and insulin (HOMA-IR calculated), PAI-1, IL-6, TNFα, adiponectin, and leptin levels were determined. C/EBPβ and PPARγ-1/2 mRNA levels were more expressed in the OM (0.001<p<0.05). ME showed the highest expression of C/EBPα, SREBP-1c, DGAT-2, and leptin and the lowest of SCD1, LXRα, VEGFα, and LOX (0.001<p<0.05). COL6A3 expression was higher in the ME and RL (p<0.001). COL6A3 expression was negatively associated with IR indices in the RL (0.01<p<0.05) and with fasting glycemia and HOMA-IR in the OM (0.001<p<0.05). VEGFα expression was positively related to TNFα and PAI-1 in the RL (0.001<p<0.05) and to PAI-1 in the OM (p<0.05) and negatively to PAI-1 in the ME (p<0.001). Fibrosis gene expression correlated negatively with inflammation in RL and OM (0.001<p<0.05) and positively with PAI-1 in the ME (0.001<p<0.05). The varying relationships of gene expression profiles with selected IR indices and inflammation biomarkers further suggest these fat depots have distinct contributions to overall health in premenopausal women with severe obesity.
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Affiliation(s)
- Andrée-Anne Clément
- Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec (CRIUCPQ), Quebec, Canada.,Département de Biochimie et Génomique Fonctionnelle, Faculté de médecine et sciences de la santé, Université de Sherbrooke, Sherbrooke, Canada
| | - Michel Lacaille
- Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec (CRIUCPQ), Quebec, Canada
| | - Mohamed Amine Lounis
- Centre de Recherche du Centre Hospitalier Universitaire de Montréal (CRCHUM), Institut du Cancer de Montréal (ICM), Montreal, Quebec, Canada
| | - Laurent D Biertho
- Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec (CRIUCPQ), Quebec, Canada.,Département de Chirurgie, Faculté de Médecine, Université Laval, Quebec, Canada
| | - Denis Richard
- Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec (CRIUCPQ), Quebec, Canada.,Département de Physiologie, Faculté de Médecine, Université Laval, Quebec, Canada
| | - Isabelle Lemieux
- Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec (CRIUCPQ), Quebec, Canada
| | - Jean Bergeron
- Axe Endocrinologie et Néphrologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec (CHUL), Québec, Canada
| | - Catherine Mounier
- Département des Sciences Biologiques et Centre d'Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois (CERMO-FC), Université du Québec À Montréal, Montreal, Canada
| | - Denis R Joanisse
- Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec (CRIUCPQ), Quebec, Canada.,Département de Kinésiologie, Faculté de médecine, Université Laval, Quebec, Canada
| | - Pascale Mauriège
- Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec (CRIUCPQ), Quebec, Canada. .,Département de Kinésiologie, Faculté de médecine, Université Laval, Quebec, Canada.
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15
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Gonias SL. Plasminogen activator receptor assemblies in cell signaling, innate immunity, and inflammation. Am J Physiol Cell Physiol 2021; 321:C721-C734. [PMID: 34406905 DOI: 10.1152/ajpcell.00269.2021] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are serine proteases and major activators of fibrinolysis in mammalian systems. Because fibrinolysis is an essential component of the response to tissue injury, diverse cells, including cells that participate in the response to injury, have evolved receptor systems to detect tPA and uPA and initiate appropriate cell-signaling responses. Formation of functional receptor systems for the plasminogen activators requires assembly of diverse plasma membrane proteins, including but not limited to: the urokinase receptor (uPAR); integrins; N-formyl peptide receptor-2 (FPR2), receptor tyrosine kinases (RTKs), the N-methyl-d-aspartate receptor (NMDA-R), and low-density lipoprotein receptor-related protein-1 (LRP1). The cell-signaling responses elicited by tPA and uPA impact diverse aspects of cell physiology. This review describes rapidly evolving knowledge regarding the structure and function of plasminogen activator receptor assemblies. How these receptor assemblies regulate innate immunity and inflammation is then considered.
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Affiliation(s)
- Steven L Gonias
- Department of Pathology, University of California, San Diego, California
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16
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Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine? Int J Mol Sci 2021; 22:ijms22126445. [PMID: 34208585 PMCID: PMC8235268 DOI: 10.3390/ijms22126445] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 06/03/2021] [Accepted: 06/10/2021] [Indexed: 12/17/2022] Open
Abstract
Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.
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17
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Pedro Ferreira J, Pitt B, Zannad F. Histone deacetylase inhibitors for cardiovascular conditions and healthy longevity. THE LANCET. HEALTHY LONGEVITY 2021; 2:e371-e379. [DOI: 10.1016/s2666-7568(21)00061-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/19/2021] [Accepted: 03/11/2021] [Indexed: 10/21/2022] Open
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18
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Levine JA, Olivares S, Miyata T, Vaughan DE, Henkel AS. Inhibition of PAI-1 Promotes Lipolysis and Enhances Weight Loss in Obese Mice. Obesity (Silver Spring) 2021; 29:713-720. [PMID: 33594826 PMCID: PMC8842994 DOI: 10.1002/oby.23112] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/30/2020] [Accepted: 12/14/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVE This study investigates the therapeutic potential of a small molecule inhibitor of plasminogen activator inhibitor-1 (PAI-1), TM5441, in reversing diet-induced obesity in mice. METHODS Wild-type C57BL/6J mice were fed a high-fat high-sugar (HFHS) diet for 8 weeks to induce obesity. After the first 8 weeks, TM5441 was added to the diet for an additional 8 weeks. In order to determine the efficacy of PAI-1 inhibition in conjunction with dietary modification, mice were fed an HFHS diet for 8 weeks to induce obesity and were then switched to a low-fat diet with or without TM5441 for an additional 2 to 8 weeks. RESULTS Obese mice showed weight reduction and significant improvement in hepatic steatosis when TM5441 was added to the HFHS diet. Obese mice that were treated with TM5441 in conjunction with dietary modification showed enhanced weight loss and a more rapid reversal of hepatic steatosis compared with obese mice treated with dietary modification alone. The enhanced weight loss among mice treated with TM5441 was associated with increased adipose tissue expression of adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, and phosphorylated perilipin-1 as well as induction of adipose tissue lipolysis. CONCLUSIONS Pharmacologic PAI-1 inhibition stimulates adipose tissue lipolysis and enhances weight loss in obese mice.
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Affiliation(s)
- Joshua A. Levine
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Shantel Olivares
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
- Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL
| | - Toshio Miyata
- Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Douglas E. Vaughan
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Anne S. Henkel
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
- Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL
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19
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Sang M, Fu Y, Wei C, Yang J, Qiu X, Ma J, Qin C, Wu F, Zhou X, Yang T, Sun M. Comparison of biomarkers of endothelial dysfunction and microvascular endothelial function in patients with primary aldosteronism and essential hypertension. J Renin Angiotensin Aldosterone Syst 2021; 22:1470320321999491. [PMID: 33678006 PMCID: PMC8164554 DOI: 10.1177/1470320321999491] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Introduction: Studies have shown that primary aldosteronism (PA) has a higher risk of
cardiovascular events than essential hypertension (EH). Endothelial
dysfunction is an independent predictor of cardiovascular events. Whether PA
and EH differ in the endothelial dysfunction is uncertain. Our study was
designed to investigate the levels of biomarkers of endothelial dysfunction
(Asymmetric dimethylarginine, ADMA; E-selectin, and Plasminogen activator
inhibitor-1, PAI-1) and assess the microvascular endothelial function in
patients with PA and EH, respectively. Methods: The biomarkers of endothelial dysfunction were measured by enzyme-linked
immunosorbent assay (ELISA). Microvascular endothelial function was
evaluated by Pulse amplitude tonometry (PAT). Results: Thirty-one subjects with EH and 36 subjects with PA including 22 with
aldosterone-producing adenoma (APA) and 14 with idiopathic
hyperaldosteronism (IHA) were enrolled in our study. The ADMA levels among
the three groups were different (APA 47.83 (27.50, 87.74) ng/ml vs EH 25.08
(22.44, 39.79) ng/ml vs IHA 26.00 (22.23, 33.75) ng/ml;
p = 0.04), however, when the APA group was
compared with EH and IHA group, there was no statistical significance (47.83
(27.50, 87.74) ng/ml vs 25.08 (22.44, 39.79) ng/ml for EH,
p = 0.11; 47.83 (27.50, 87.74) ng/ml vs
IHA 26.00 (33.75) ng/ml, p = 0.07). The
results of ADMA levels are presented as Median (p25, p75). Whereas, levels
of PAI-1 and E-selectin, microvascular endothelial function were not
significantly different between PA and EH subjects. Conclusions: Our study shows no significant differences between PA and EH in terms of
biomarkers of endothelial dysfunction and microvascular endothelial
function. The microvascular endothelial function of PA and EH patients is
comparable.
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Affiliation(s)
- Miaomiao Sang
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Fu
- Department of Nuclear Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chenmin Wei
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Yang
- School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xueting Qiu
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jingqing Ma
- School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chao Qin
- Department of Urology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Feiyan Wu
- Department of Endocrinology, The Second People's Hospital of Wuxi, Wuxi, Jiangsu, China
| | - Xueling Zhou
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tao Yang
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Min Sun
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
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20
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Sánchez-Marín P, Vidal-Liñán L, Fernández-González LE, Montes R, Rodil R, Quintana JB, Carrera M, Mateos J, Diz AP, Beiras R. Proteomic analysis and biochemical alterations in marine mussel gills after exposure to the organophosphate flame retardant TDCPP. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2021; 230:105688. [PMID: 33316748 DOI: 10.1016/j.aquatox.2020.105688] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 10/27/2020] [Accepted: 11/15/2020] [Indexed: 06/12/2023]
Abstract
Organophosphate flame retardants (OPFRs) are (re-)emergent environmental pollutants increasingly being used because of the restriction of other flame retardants. The chlorinated OPFR, tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is among those of highest environmental concern, but its potential effects in the marine environment have rarely been investigated. We exposed a widely used sentinel marine mussel species, Mytilus galloprovincialis, to 10 μg L-1 of TDCPP during 28 days and studied: (i) the kinetics of bioaccumulation and elimination of the compound, (ii) the effect on two molecular biomarkers, glutathione S-transferase (GST) and acetylcholinesterase (AChE) activities, and (iii) proteomic alterations in the gills, following an isobaric labeling quantitative shotgun proteomic approach, at two exposure times (7 and 28 days). Uptake and elimination of TDCPP by mussels were very fast, and the bioconcentration factor of this compound in mussels was 147 L kgww-1, confirming that this compound is not very bioaccumulative, as predicted by its chemical properties. GST activity was not affected by TDCPP exposure, but AChE activity was inhibited by TDCPP at both 7 and 28 days of exposure. Proteomic analysis revealed subtle effects of TDCPP in mussel gills, since few proteins (less than 2 % of the analysed proteome) were significantly affected by TDCPP, and effect sizes were low. The most relevant effects detected were the up-regulation of epimerase family protein SDR39U1, an enzyme that could be involved in detoxification processes, at both exposure times, and the down-regulation of receptor-type tyrosine-protein phosphatase N2-like (PTPRN2) after 7 days of exposure, which is involved in neurotransmitter secretion and might be related to the neurotoxicity described for this compound. Exposure time rather than TDCPP exposure was the most important driver of protein abundance changes, with 33 % of the proteome being affected by this factor, suggesting that stress caused by laboratory conditions could be an important confounding factor that needs to be controlled in similar ecotoxicology studies. Proteomic data are available via ProteomeXchange with identifier PXD019720.
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Affiliation(s)
- Paula Sánchez-Marín
- Department of Ecology and Animal Biology, University of Vigo, 36310 Vigo, Galicia, Spain; Centro Oceanográfico de Vigo, Instituto Español de Oceanografía, 36390 Vigo, Spain.
| | - Leticia Vidal-Liñán
- Department of Ecology and Animal Biology, University of Vigo, 36310 Vigo, Galicia, Spain; Centro Oceanográfico de Vigo, Instituto Español de Oceanografía, 36390 Vigo, Spain
| | - Laura Emilia Fernández-González
- Department of Ecology and Animal Biology, University of Vigo, 36310 Vigo, Galicia, Spain; Department of Biochemistry, Genetics and Immunology, University of Vigo, 36310 Vigo, Spain; Marine Research Centre, University of Vigo (CIM-UVIGO), Isla de Toralla, Vigo, Spain
| | - Rosa Montes
- Department of Analytical Chemistry, Nutrition and Food Sciences, Institute of Research in Chemical and Biological Analysis (IAQBUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Rosario Rodil
- Department of Analytical Chemistry, Nutrition and Food Sciences, Institute of Research in Chemical and Biological Analysis (IAQBUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - José Benito Quintana
- Department of Analytical Chemistry, Nutrition and Food Sciences, Institute of Research in Chemical and Biological Analysis (IAQBUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Mónica Carrera
- Institute of Marine Research (IIM), Spanish National Research Council (CSIC), 36208 Vigo, Spain
| | - Jesús Mateos
- Institute of Marine Research (IIM), Spanish National Research Council (CSIC), 36208 Vigo, Spain
| | - Angel P Diz
- Department of Biochemistry, Genetics and Immunology, University of Vigo, 36310 Vigo, Spain; Marine Research Centre, University of Vigo (CIM-UVIGO), Isla de Toralla, Vigo, Spain
| | - Ricardo Beiras
- Department of Ecology and Animal Biology, University of Vigo, 36310 Vigo, Galicia, Spain; Marine Research Centre, University of Vigo (CIM-UVIGO), Isla de Toralla, Vigo, Spain
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21
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van IJzendoorn DGP, Salvatori DCF, Cao X, van den Hil F, Briaire-de Bruijn IH, de Jong D, Mei H, Mummery CL, Szuhai K, Bovée JVMG, Orlova VV. Vascular Tumor Recapitulated in Endothelial Cells from hiPSCs Engineered to Express the SERPINE1-FOSB Translocation. CELL REPORTS MEDICINE 2020; 1:100153. [PMID: 33377124 PMCID: PMC7762773 DOI: 10.1016/j.xcrm.2020.100153] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 08/10/2020] [Accepted: 11/16/2020] [Indexed: 12/13/2022]
Abstract
Chromosomal translocations are prevalent among soft tissue tumors, including those of the vasculature such as pseudomyogenic hemangioendothelioma (PHE). PHE shows endothelial cell (EC) features and has a tumor-specific t(7;19)(q22;q13) SERPINE1-FOSB translocation, but is difficult to study as no primary tumor cell lines have yet been derived. Here, we engineer the PHE chromosomal translocation into human induced pluripotent stem cells (hiPSCs) using CRISPR/Cas9 and differentiate these into ECs (hiPSC-ECs) to address this. Comparison of parental with PHE hiPSC-ECs shows (1) elevated expression of FOSB, (2) higher proliferation and more tube formation but lower endothelial barrier function, (3) invasive growth and abnormal vessel formation in mice after transplantation, and (4) specific transcriptome alterations reflecting PHE and indicating PI3K-Akt and MAPK signaling pathways as possible therapeutic targets. The modified hiPSC-ECs thus recapitulate functional features of PHE and demonstrate how these translocation models can be used to understand tumorigenic mechanisms and identify therapeutic targets.
SERPINE1-FOSB translocation in hiPSC to model the vascular tumor PHE CRISPR/Cas9-mediated gene targeting to engineer hiPSCSERPINE1-FOSB hiPSC-ECsSERPINE1-FOSB show increased FOSB expression Functional features of PHE recapitulated by hiPSC-ECsSERPINE1-FOSB
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Affiliation(s)
| | - Daniela C F Salvatori
- Central Laboratory Animal Facility, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
| | - Xu Cao
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
| | - Francijna van den Hil
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
| | | | - Danielle de Jong
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
| | - Hailiang Mei
- Sequencing Analysis Support Core, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
| | - Christine L Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
| | - Karoly Szuhai
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
| | - Judith V M G Bovée
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
| | - Valeria V Orlova
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
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22
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Yousef AA, Mohamed FY, Boraey NF, Akeel NE, Soliman AA, Waked NM, Hashem MIA, Shehata H, Fahmy DS, Ismael A, Ibrahim LM, Ibrahim MAM, Salem HF, Yousry SM, Osman SF, Fouad RA, Enan ET, Attia MA, Afify MR, Zeidan NMS, Nashat M. Association of Plasminogen Activator Inhibitor 1 (PAI-1) 4G/5G Polymorphism and Susceptibility to SLE in Egyptian Children and Adolescents: A Multicenter Study. J Inflamm Res 2020; 13:1103-1111. [PMID: 33363394 PMCID: PMC7754263 DOI: 10.2147/jir.s277373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/27/2020] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Plasminogen activator inhibitor-1 (PAI-1) is a key molecule residing at the nexus between thrombosis and inflammatory processes. Recently, PAI-1 and its gene expression have emerged as a potential candidate for autoimmune disorders such as SLE. OBJECTIVE To investigate whether the PAI-1 4G/5G polymorphism at position -675 could be a genetic marker for susceptibility to childhood-onset SLE and development of lupus nephritis among Egyptian children and adolescents. METHODS Three hundred fifty patients diagnosed with childhood-onset SLE and 350 well-matched healthy controls were included in this multi-center study. All subjects were genotyped for the PAI-1 promoter 4G/5G polymorphism at position -675 using PCR- restriction fragment length polymorphism (RFLP). Serum PAI-1 levels were measured by ELISA. RESULTS The PAI-1 (- 675) 4G/4G genotype was more represented in c-SLE patients, as compared to the control group (38% vs 23%; OR =2.7; [95% CI: 1.47-2.9]; P < 0.001). Patients carrying the PAI-1 4G/4G genotype or 4G allele were more likely to develop lupus nephritis (OR: 3.38; [95% CI: 1.9-5.9]; P <0.001, for the 4G/4G genotype and OR: 2.6; [95% CI: 1.85-3.67]; for the 4G allele; P < 0.01). The PAI-1 4G/4G genotype was associated with higher PAI-1 serum concentrations (mean; 86.6±22.7 ng/mL) as compared to those with a 4G/5G genotype (mean; 48.3±16.5 ng/mL) and the lowest for the 5G/5G genotype (mean; 34.7±11.4 ng/mL); P = 0.004. CONCLUSION The PAI-1 4G/5G polymorphism may confer susceptibility to childhood-onset SLE and development of lupus nephritis among Egyptian children and adolescents. Moreover, the PAI-1 4G/4G genotype and 4G allele were associated with higher PAI-1 serum levels and higher disease activity scores.
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Affiliation(s)
- Aly A Yousef
- Department of Pediatrics, Faculty of Medicine, Helwan University, Helwan, Egypt
| | - Faisal Y Mohamed
- Department of Pediatrics, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
| | - Naglaa F Boraey
- Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Nagwa E Akeel
- Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Attia A Soliman
- Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Nevin M Waked
- Department of Pediatrics, Faculty of Medicine, October 6 University, October 6, Egypt
| | - Mustafa I A Hashem
- Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Hassan Shehata
- Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Dalia S Fahmy
- Department of Rheumatology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Ali Ismael
- Department of Internal Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Lamya M Ibrahim
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mohamed A M Ibrahim
- Department of Clinical Pathology, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Hanan F Salem
- Department of Anesthesia, Faculty of Medicine, Banha University, Banha, Egypt
| | - Sherif M Yousry
- Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Sherif F Osman
- Department of Radiology, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Rania A Fouad
- Department of Medical Biochemistry, College of Medicine, El-Mareefa University, Riyadh, Kingdom of Saudi Arabia
- Department of Medical Biochemistry, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Eman T Enan
- Department of Pathology, College of Medicine, El-Mareefa University, Riyadh, Kingdom of Saudi Arabia
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Mohammed A Attia
- Department of Clinical Pharmacology, College of Medicine, El-Mareefa University, Riyadh, Kingdom of Saudi Arabia
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Mona R Afify
- Department of Medical microbiology and Parasitology, Faculty of Medicine, University of Jeddah, Jeddah, 21589, Saudia Arabia
| | - Nancy M S Zeidan
- Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Nashat
- Department of Pediatrics, Faculty of Medicine, Aswan University, Aswan, Egypt
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Olivares S, Henkel AS. Endoplasmic reticulum stress induces hepatic plasminogen activator inhibitor 1 in murine nonalcoholic steatohepatitis. FASEB Bioadv 2020; 2:695-704. [PMID: 33336157 PMCID: PMC7734423 DOI: 10.1096/fba.2020-00056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/19/2020] [Accepted: 08/25/2020] [Indexed: 01/20/2023] Open
Abstract
Plasminogen activator inhibitor 1 (PAI-1) is a stress-responsive gene that is highly induced in nonalcoholic steatohepatitis (NASH). Endoplasmic reticulum (ER) stress is a salient feature of NASH, yet it is unknown whether ER stress contributes to hepatic PAI-1 induction in this disorder. Therefore, we aimed to (a) establish the role of ER stress in the regulation of hepatic Pai-1 expression, and (b) determine whether induction of Pai-1 in murine NASH is driven by ER stress. Hepatic Pai-1 expression was measured in C57BL/6 J mice and human HepG2 cells subjected to acute or prolonged pharmacologic ER stress. We found that hepatic Pai-1 expression was acutely suppressed in murine liver in response to severe ER stress followed by marked induction during the recovery phase of the ER stress response. Hepatic Pai-1 expression was induced in response to prolonged low-grade ER stress in mice. Induction of PAI-1 by ER stress in HepG2 cells was prevented by pharmacologic inhibition of MEK1/ERK signaling or by siRNA-mediated knockdown of XBP1, mediators of the recovery response to ER stress. Inhibiting ER stress with 4-phenylbutyric acid prevented hepatic Pai-1 induction in mice with diet-induced steatohepatitis. We conclude that hepatic Pai-1 is induced by ER stress via a pathway involving XBP1 and MEK1/ERK signaling, and induction of hepatic Pai-1 in murine NASH is mediated by ER stress. These data implicate ER stress as a novel mechanistic link between Pai-1 induction and NASH.
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Affiliation(s)
- Shantel Olivares
- Department of MedicineNorthwestern UniversityChicagoILUSA
- Jesse Brown VA Medical CenterChicagoILUSA
| | - Anne S. Henkel
- Department of MedicineNorthwestern UniversityChicagoILUSA
- Jesse Brown VA Medical CenterChicagoILUSA
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24
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Bayramoglu A, Bayramoglu G, Urhan Kucuk M, Guler HI, Arpaci A. Genetic variations of renin-angiotensin and fibrinolytic systems and susceptibility to coronary artery disease: a population genetics perspective. Minerva Cardiol Angiol 2020; 70:16-24. [PMID: 32989965 DOI: 10.23736/s2724-5683.20.05212-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Genetic predisposition is an important risk factor in coronary artery disease (CAD).This study was conducted to determine the polymorphism frequencies of the plasminogen activator inhibitor-1(PAI-1) gene 4G/5G, angiotensin-converting enzyme (ACE) gene I/D, and angiotensin II type 1 receptor (AT1) gene A1166C genotypes and to examine the role of these polymorphisms in CAD. METHODS Genomic DNAs obtained from 260 subjects (130 CAD patients and 130 control) were used in the study. ACE I/D and PAI-1 4G/5G polymorphism genotypes were determined using polymerase chain reaction (PCR) and electrophoresis. AT-1 A1166C polymorphism was determined using the PCR, restriction fragment length polymorphism (RFLP) and electrophoresis. The products amplified from AT1 gene by PCR were cut with HindIII restriction endonuclease and then analyzed by 2% agarose gel electrophoresis. The results were statistically analyzed with the chi-square test, Mann-Whitney U test, and independent two-sample t-test. RESULTS Allele frequencies showed statistically significant differences between the patient and control groups. There was no statistically significant difference in ACEI/D genotype frequencies between the twogroups. Likewise, no statistically significant difference was found in the AT1 A1166C genotype frequencies; however, a statistically significant difference was found in allele frequencies. The PAI-1 4G/5G genotype frequency was significantly higher in the patient group. CONCLUSIONS While there is a relationship between of PAI-1 gene 4G/5G polymorphism and CAD, ACE gene I/D and AT1 gene A1166C polymorphisms are not related. PAI-1 gene homozygous genotypes may be considered as a prognostic marker for CAD patients.
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Affiliation(s)
- Aysegul Bayramoglu
- Department of Molecular Biology and Genetics, Institute of Science, Artvin Coruh University, Artvin, Turkey - .,Department of Nutrition and Dietetics, Faculty of Health Sciences, Artvin Coruh University, Artvin, Turkey -
| | - Gokhan Bayramoglu
- Department of Molecular Biology and Genetics, Institute of Science, Artvin Coruh University, Artvin, Turkey.,Department of Occupational Health and Safety, Faculty of Health Sciences, Artvin Coruh University, Artvin, Turkey
| | - Meral Urhan Kucuk
- Department of Medical Biology, Faculty of Medicine, Mustafa Kemal University, Antakya, Turkey
| | - Halil I Guler
- Department of Molecular Biology and Genetics, Faculty of Science, Karadeniz Technical University, Trabzon, Turkey
| | - Abdullah Arpaci
- Department of Medical Biochemistry, Faculty of Medicine, Mustafa Kemal University, Antakya, Turkey
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25
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Buzelle SL, Przygodda F, Rossi-Valentim R, Ferreira GN, Garófalo MAR, Alves VM, Chaves VE, Navegantes LCC, Kettelhut IDC. Activation of adipose tissue glycerokinase contributes to increased white adipose tissue mass in mice fed a high-fat diet. Endocrine 2020; 69:79-91. [PMID: 32297203 DOI: 10.1007/s12020-020-02288-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 03/25/2020] [Indexed: 01/04/2023]
Abstract
PURPOSE Investigate the pathways of glycerol-3-P (G3P) generation for triacylglycerol (TAG) synthesis in retroperitoneal (RWAT) and epididymal (EWAT) white adipose tissues from high-fat diet (HFD)-fed mice. METHODS Mice were fed for 8 weeks a HFD and glycolysis, glyceroneogenesis and direct phosphorylation of glycerol were evaluated, respectively, by 2-deoxyglucose uptake, phosphoenolpyruvate carboxykinase (PEPCK-C) activity and pyruvate incorporation into TAG-glycerol, and glycerokinase activity and glycerol incorporation into TAG-glycerol in both tissues. RESULTS HFD increased body and adipose tissue mass and serum levels of glucose and insulin, which were accompanied by glucose intolerance. RWAT and EWAT from HFD-fed mice had increased rates of de novo fatty acid (FA) synthesis (52% and 255%, respectively). HFD increased lipoprotein lipase (LPL) activity and content in EWAT (107%), but decreased in RWAT (79%). HFD decreased the lipolytic response to norepinephrine (57%, RWAT and 25%, EWAT), β3-adrenoceptor content (50%), which was accompanied by a decrease in phosphorylated-hormone-sensitive lipase (~80%) and phosphorylated-adipocyte triacylglycerol lipase (~60%) in both tissues. HFD decreased the in vitro rates of glucose uptake (3.5- and 6-fold), as well as in glyceride-glycerol synthesis from pyruvate (~3.5-fold) without changes in PEPCK-C activity and content in RWAT and EWAT, but increased glycerokinase activity(~3-fold) and content (90 and 40%) in both tissues. CONCLUSION The data suggest that direct phosphorylation of glycerol by glycerokinase may be responsible for maintaining the supply of G3P for the existing rates of FA esterification and TAG synthesis in RWAT and EWAT from HFD-fed mice, contributing, along with a lower lipolytic response to norepinephrine, to higher adiposity.
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Affiliation(s)
- Samyra Lopes Buzelle
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Franciele Przygodda
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Rafael Rossi-Valentim
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | | | | | - Vani Maria Alves
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Valéria Ernestânia Chaves
- Laboratory of Physiology, Federal University of São João del-Rei, Divinópolis, Minas Gerais, Brazil.
| | | | - Isis do Carmo Kettelhut
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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26
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Mira MF, Anwar GM, Sarry EL-Din AM, Megahed SM. Assessment of plasminogen activator inhibitor-1 in obese Egyptian children. EGYPTIAN PEDIATRIC ASSOCIATION GAZETTE 2020. [DOI: 10.1186/s43054-019-0012-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Plasminogen activator inhibitor-1 (PAI-1) is mainly produced in the liver and in the adipose tissue. Normal fibrin clearance mechanisms were found to be affected by high plasma PAI-1 levels and thus increases risk of thrombosis. The aim of the current study was to expound the childhood obesity effect on circulating PAI-1 and interpret the relation of PAI-1 to metabolic syndrome. This cross-sectional study was conducted on 43 obese children following in the Children Hospital and compared to 44 healthy sex- and age-matched controls. All recruited cohort are subjected to anthropometric measurements: weight, height, BMI, waist circumference, hip circumference, and skin fold thickness (biceps, triceps, and subscapular), and laboratory investigations in the form of lipid profile, fasting blood sugar, fasting insulin, insulin resistance estimated by HOMA-IR, and plasminogen activator inhibitor-1.
Results
The level of plasminogen activator inhibitor-1 in the obese group was significantly higher than that in the control group (47.98 ± 17.42 vs. 28.00 ± 11.35 respectively). PAI-1 showed positive significant correlation to anthropometric measurements: BMI (p = 0.000), weight (p = 0.000), biceps skin fold thickness (p = 0.04), triceps skin fold thickness (p = 0.4), and subscapular skin fold thickness (p = 0.04). Also, a significant positive correlation was found between PAI-1 and systolic (p = 0.000) and diastolic blood pressure (p = 0.04). Positive correlations were found between PAI-1 and cholesterol (p = 0.000), triglycerides (p = 0.02), LDL-c (p = 0.000), insulin (p = 0.000), and HOMA-IR (r = 0.5, p = 0.02).
Conclusion
Fat mass accumulation is related to high PAI-1 levels, which might in turn contribute to cardiovascular risk. Plasminogen Activator Inhibitor-1 is a good predictive test for metabolic syndrome in obese children.
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Singh AP, Singh R, Verma SS, Rai V, Kaschula CH, Maiti P, Gupta SC. Health benefits of resveratrol: Evidence from clinical studies. Med Res Rev 2019; 39:1851-1891. [PMID: 30741437 DOI: 10.1002/med.21565] [Citation(s) in RCA: 343] [Impact Index Per Article: 57.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 12/07/2018] [Accepted: 01/19/2019] [Indexed: 12/14/2022]
Abstract
Resveratrol is a polyphenolic nutraceutical that exhibits pleiotropic activities in human subjects. The efficacy, safety, and pharmacokinetics of resveratrol have been documented in over 244 clinical trials, with an additional 27 clinical trials currently ongoing. Resveretrol is reported to potentially improve the therapeutic outcome in patients suffering from diabetes mellitus, obesity, colorectal cancer, breast cancer, multiple myeloma, metabolic syndrome, hypertension, Alzheimer's disease, stroke, cardiovascular diseases, kidney diseases, inflammatory diseases, and rhinopharyngitis. The polyphenol is reported to be safe at doses up to 5 g/d, when used either alone or as a combination therapy. The molecular basis for the pleiotropic activities of resveratrol are based on its ability to modulate multiple cell signaling molecules such as cytokines, caspases, matrix metalloproteinases, Wnt, nuclear factor-κB, Notch, 5'-AMP-activated protein kinase, intercellular adhesion molecule, vascular cell adhesion molecule, sirtuin type 1, peroxisome proliferator-activated receptor-γ coactivator 1α, insulin-like growth factor 1, insulin-like growth factor-binding protein 3, Ras association domain family 1α, pAkt, vascular endothelial growth factor, cyclooxygenase 2, nuclear factor erythroid 2 like 2, and Kelch-like ECH-associated protein 1. Although the clinical utility of resveratrol is well documented, the rapid metabolism and poor bioavailability have limited its therapeutic use. In this regard, the recently produced micronized resveratrol formulation called SRT501, shows promise. This review discusses the currently available clinical data on resveratrol in the prevention, management, and treatment of various diseases and disorders. Based on the current evidence, the potential utility of this molecule in the clinic is discussed.
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Affiliation(s)
- Akhand Pratap Singh
- School of Materials Science and Technology, Indian Institute of Technology (BHU), Varanasi, India
| | - Rachna Singh
- Department of Botany, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Sumit Singh Verma
- Laboratory for Translational Cancer Research, Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Vipin Rai
- Laboratory for Translational Cancer Research, Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Catherine H Kaschula
- Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, South Africa
| | - Pralay Maiti
- School of Materials Science and Technology, Indian Institute of Technology (BHU), Varanasi, India
| | - Subash Chandra Gupta
- Laboratory for Translational Cancer Research, Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
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Longo CM, Higgins PJ. Molecular biomarkers of Graves' ophthalmopathy. Exp Mol Pathol 2018; 106:1-6. [PMID: 30414981 DOI: 10.1016/j.yexmp.2018.11.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/15/2018] [Accepted: 11/07/2018] [Indexed: 12/25/2022]
Abstract
Graves' ophthalmopathy (GO), a complication of Graves' disease (GD), is typified by orbital inflammation, ocular tissue expansion and remodeling and, ultimately, fibrosis. Orbital fibroblasts are key effectors of GO pathogenesis exhibiting exaggerated inflammatory and fibroproliferative responses to cytokines released by infiltrating immune cells. Activated orbital fibroblasts also produce inflammatory mediators that contribute to disease progression, facilitate the orbital trafficking of monocytes and macrophages, promote differentiation of matrix-producing myofibroblasts and stimulate accumulation of a hyaluronan-rich stroma, which leads to orbital tissue edema and fibrosis. Proteomic and transcriptome profiling of the genomic response of ocular and non-ocular fibroblasts to INF-γ and TGF-β1 focused on identification of translationally-relevant therapeutic candidates. Induction of plasminogen activator inhibitor-1 (PAI-1, SERPINE1), a clade E member of the serine protease inhibitor (SERPIN) gene family and a prominent regulator of the pericellular proteolytic microenvironment, was one of the most highly up-regulated proteins in INF-γ- or TGF-β1-stimulated GO fibroblasts as well as in severe active GD compared to patients without thyroid disease. PAI-1 has multifunctional roles in inflammatory and fibrotic processes that impact tissue remodeling, immune cell trafficking and survival as well as signaling through several receptor systems. This review focuses on the pathophysiology of the GO fibroblast and possible targets for effective drug therapy.
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Affiliation(s)
- Christine M Longo
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, New York 12208, United States
| | - Paul J Higgins
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, New York 12208, United States.
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29
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Henkel AS, Khan SS, Olivares S, Miyata T, Vaughan DE. Inhibition of Plasminogen Activator Inhibitor 1 Attenuates Hepatic Steatosis but Does Not Prevent Progressive Nonalcoholic Steatohepatitis in Mice. Hepatol Commun 2018; 2:1479-1492. [PMID: 30556037 PMCID: PMC6287480 DOI: 10.1002/hep4.1259] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 08/24/2018] [Indexed: 01/08/2023] Open
Abstract
Plasminogen activator inhibitor 1 (PAI‐1), an essential regulator of fibrinolysis, is increasingly implicated in the pathogenesis of metabolic disorders, such as obesity and nonalcoholic fatty liver disease (NAFLD). Pharmacologic inhibition of PAI‐1 is emerging as a highly promising therapeutic strategy for obesity and its sequelae. Given the well‐established profibrotic function of PAI‐1, we considered whether PAI‐1 may serve as a target for antifibrotic therapy in nonalcoholic steatohepatitis (NASH). We therefore determined the effect of genetic Pai‐1 deletion and pharmacologic PAI‐1 inhibition on the development of NASH‐related fibrosis in mice. Pai‐1 knockout (Pai‐1–/–) and wild‐type control (Pai‐1+/+) mice were fed a high‐fat/high‐cholesterol high‐sugar (HFHS) diet or a methionine‐ and choline‐deficient (MCD) diet to induce steatohepatitis with fibrosis. PAI‐1 was pharmacologically inhibited using the small molecule inhibitor TM5441 in wild‐type C57BL/6 mice fed an HFHS or MCD diet. Either genetic deletion of Pai‐1 or pharmacologic inhibition of PAI‐1 attenuated MCD diet‐induced hepatic steatosis but did not prevent hepatic inflammation or fibrosis. Targeted inhibition of PAI‐1 conferred transient protection from HFHS diet‐induced obesity and hepatic steatosis, an effect that was lost with prolonged exposure to the obesigenic diet. Neither genetic deletion of Pai‐1 nor pharmacologic inhibition of PAI‐1 prevented HFHS diet‐induced hepatic inflammation or fibrosis. Conclusion:Pai‐1 regulates hepatic lipid accumulation but does not promote NASH progression. The PAI‐1 inhibitor TM5441 effectively attenuates diet‐induced obesity and hepatic steatosis but does not prevent NASH‐related fibrosis in mice.
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Affiliation(s)
- Anne S Henkel
- Department of Medicine Northwestern University Chicago IL.,Jesse Brown VA Medical Center Chicago IL
| | - Sadiya S Khan
- Department of Medicine Northwestern University Chicago IL
| | | | - Toshio Miyata
- Department of Medicine Northwestern University Chicago IL
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Luteolin-Enriched Artichoke Leaf Extract Alleviates the Metabolic Syndrome in Mice with High-Fat Diet-Induced Obesity. Nutrients 2018; 10:nu10080979. [PMID: 30060507 PMCID: PMC6115887 DOI: 10.3390/nu10080979] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 07/23/2018] [Accepted: 07/26/2018] [Indexed: 12/19/2022] Open
Abstract
This current study aimed to elucidate the effects and possible underlying mechanisms of long-term supplementation with dietary luteolin (LU)-enriched artichoke leaf (AR) in high-fat diet (HFD)-induced obesity and its complications (e.g., dyslipidemia, insulin resistance, and non-alcoholic fatty liver disease) in C57BL/6N mice. The mice were fed a normal diet, an HFD, or an HFD plus AR or LU for 16 weeks. In the HFD-fed mice, AR decreased the adiposity and dyslipidemia by decreasing lipogenesis while increasing fatty acid oxidation, which contributed to better hepatic steatosis. LU also prevented adiposity and hepatic steatosis by suppressing lipogenesis while increasing biliary sterol excretion. Moreover, AR and LU prevented insulin sensitivity by decreasing the level of plasma gastric inhibitory polypeptide and activity of hepatic glucogenic enzymes, which may be linked to the lowering of inflammation as evidenced by the reduced plasma interleukin (IL)-6, IL-1β, and plasminogen activator inhibitor-1 levels. Although the anti-metabolic syndrome effects of AR and LU were similar, the anti-adiposity and anti-dyslipidemic effects of AR were more pronounced. These results in mice with diet-induced obesity suggest that long-term supplementation with AR can prevent adiposity and related metabolic disorders such as dyslipidemia, hepatic steatosis, insulin resistance, and inflammation.
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31
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Gonias SL, Banki MA, Gilder AS, Azmoon P, Campana WM, Mantuano E. PAI1 blocks NMDA receptor-mediated effects of tissue-type plasminogen activator on cell signaling and physiology. J Cell Sci 2018; 131:jcs.217083. [PMID: 29930084 DOI: 10.1242/jcs.217083] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 05/29/2018] [Indexed: 01/08/2023] Open
Abstract
The fibrinolysis proteinase tissue-type plasminogen activator (tPA, also known as PLAT) triggers cell signaling and regulates cell physiology. In PC12 cells, Schwann cells and macrophages, the N-methyl-D-aspartate receptor (NMDA-R) mediates tPA signaling. Plasminogen activator inhibitor-1 (PAI1, also known as SERPINE1) is a rapidly acting inhibitor of tPA enzyme activity. Although tPA-initiated cell signaling is not dependent on its enzyme active site, we show that tPA signaling is neutralized by PAI1. In PC12 cells, PAI1 blocked the ERK1/2 activation mediated by tPA as well as neurite outgrowth. In Schwann cells, PAI1 blocked tPA-mediated ERK1/2 activation and cell migration. In macrophages, PAI1 blocked the ability of tPA to inhibit IκBα phosphorylation and cytokine expression. The cell signaling activity of tPA-PAI1 complex was rescued when the complex was formed with PAI1R76E, which binds to LRP1 with decreased affinity, by pre-treating cells with the LRP1 antagonist receptor-associated protein and upon LRP1 gene silencing. The inhibitory role of LRP1 in tPA-PAI1 complex-initiated cell signaling was unanticipated given the reported role of LRP1 as an NMDA-R co-receptor in signaling responses elicited by free tPA or α2-macroglobulin. We conclude that PAI1 functions as an in-hibitor not only of the enzyme activity of tPA but also of tPA receptor-mediated activities.
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Affiliation(s)
- Steven L Gonias
- Department of Pathology, University of California San Diego, La Jolla CA 92093, USA
| | - Michael A Banki
- Department of Pathology, University of California San Diego, La Jolla CA 92093, USA
| | - Andrew S Gilder
- Department of Pathology, University of California San Diego, La Jolla CA 92093, USA
| | - Pardis Azmoon
- Department of Pathology, University of California San Diego, La Jolla CA 92093, USA
| | - Wendy M Campana
- Department of Anesthesiology and the Program in Neuroscience, University of California San Diego, La Jolla CA 92093, USA
| | - Elisabetta Mantuano
- Department of Pathology, University of California San Diego, La Jolla CA 92093, USA.,Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
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32
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Fan Q, Li H, Qin Y, Li L, Chen L, Zhang L, Lv Y, Liang D, Liang Y, Long T, Xie L, Yang H, Dong C, Zhang H. Association of SERPINE1 rs6092 with type 2 diabetes and related metabolic traits in a Chinese population. Gene 2018; 661:176-181. [PMID: 29627522 DOI: 10.1016/j.gene.2018.04.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 03/28/2018] [Accepted: 04/05/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Plasminogen activator inhibitor-1 (PAI-I), encoded by SERPINE1 gene, is a member of the serine protease inhibitor superfamily, and polymorphisms in SERPINE1 have been reported to be associated with type 2 diabetes (T2D). This study investigated whether the polymorphism in PAI-I contribute to the risk for T2D. METHODS A 1:1 case-control study was conducted to investigate the association of rs6092 in SERPINE1 with T2D and diabetes-related metabolic traits, including body mass index, waist circumference (WC), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol, low density lipoprotein cholesterol, fasting plasma glucose and glycosylated hemoglobin (HbA1c) in a Chinese population, with a total of 1572 subjects (786 T2D patients and 786 healthy controls). The polymorphism was genotyped based on MassARRAY genotyping system. RESULTS The AA genotype and A allele of rs6092 exerted a protective effect on T2D risk (odds ratio (OR) = 0.431 and 0.630, respectively). In a recessive model, we also observed the protective association of rs6092 with T2D (OR = 0.195). The above associations were only observed in men. In female patients, there was a significant difference in HbA1c level between the AA homozygotes and GG homozygotes, as well as between the AA homozygotes and combined GG and GA genotypes. In male patients, the WC level in the subjects carrying AA genotype was lower than those in the subjects with GG genotype (P = 0.000), and the association was also significant in a recessive model (P = 0.000). Additionally, there was a significant difference in TG level between the AA homozygotes and GG homozygotes (P = 0.017), as well as the AA homozygotes and combined GG and GA genotypes (P = 0.032). CONCLUSIONS Our study suggests that the A allele and AA genotype of rs6092 may protect against T2D, and have a protective effect on WC, but a negative effect on TG in men, while may contribute to a lower HbA1c level in women.
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Affiliation(s)
- Qiuyu Fan
- School of Public Health, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Hong Li
- School of General Medicine, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Yingfen Qin
- Department of Endocrine, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Li Li
- Department of Endocrine, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Lulin Chen
- School of Public Health, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Lulu Zhang
- School of Public Health, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Yingnan Lv
- School of Public Health, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Danyan Liang
- Third Affiliated Hospital of Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Yaojie Liang
- Beihai Center for Disease Prevention and Control, Beihai 536000, People's Republic of China
| | - Tianzhu Long
- School of Public Health, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Lianguang Xie
- School of Public Health, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Haisheng Yang
- School of Public Health, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Chunting Dong
- School of Public Health, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Haiying Zhang
- School of Public Health, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, People's Republic of China; Center for Genomic and Personalized Medicine, Nanning 530021, People's Republic of China.
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Jung RG, Motazedian P, Ramirez FD, Simard T, Di Santo P, Visintini S, Faraz MA, Labinaz A, Jung Y, Hibbert B. Association between plasminogen activator inhibitor-1 and cardiovascular events: a systematic review and meta-analysis. Thromb J 2018; 16:12. [PMID: 29991926 PMCID: PMC5987541 DOI: 10.1186/s12959-018-0166-4] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 03/05/2018] [Indexed: 12/17/2022] Open
Abstract
Background Small studies have implicated plasminogen activator inhibitor-1 (PAI-1) as a predictor of cardiovascular events; however, these findings have been inconsistent. We sought out to examine the potential role of PAI-1 as a marker for major adverse cardiovascular events (MACE). Methods We systematically reviewed all indexed studies examining the association between PAI-1 and MACE (defined as death, myocardial infarction, or cerebrovascular accident) or restenosis. EMBASE, Web of Science, Medline, and the Cochrane Library were searched through October 2016 to identify relevant studies, supplemented by letters to authors and review of citations. Studies reporting the results of PAI-1 antigen and/or activity levels in association with MACE in human subjects were included. Results Of 5961 articles screened, we identified 38 articles published between 1991 to 2016 that reported PAI-1 levels in 11,557 patients. In studies that examined PAI-1 antigen and activity levels, 15.1% and 29.6% of patients experienced MACE, respectively. Patients with MACE had higher PAI-1 antigen levels with a mean difference of 6.11 ng/mL (95% CI, 3.27-8.96). This finding was similar among patients with and without known coronary artery disease. Comparatively, studies that stratified by PAI-1 activity levels were not associated with MACE. In contrast, studies of coronary restenosis suggest PAI-1 antigen and activity levels are negatively associated with MACE. Conclusions Elevated plasma PAI-1 antigen levels are associated with MACE. Definitive studies are needed to ascertain if PAI-1 acts simply as a marker of risk or if it is indeed a bona fide therapeutic target. Electronic supplementary material The online version of this article (10.1186/s12959-018-0166-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Richard G Jung
- 1CAPITAL Research Group, University of Ottawa Heart Institute, 40 Ruskin Street, H-4238, Ottawa, ON K1Y 4W7 Canada.,2Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON Canada.,3Vascular Biology and Experimental Medicine Laboratory, University of Ottawa Heart Institute, Ottawa, ON Canada
| | - Pouya Motazedian
- 1CAPITAL Research Group, University of Ottawa Heart Institute, 40 Ruskin Street, H-4238, Ottawa, ON K1Y 4W7 Canada
| | - F Daniel Ramirez
- 1CAPITAL Research Group, University of Ottawa Heart Institute, 40 Ruskin Street, H-4238, Ottawa, ON K1Y 4W7 Canada.,4Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON Canada.,5School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON Canada
| | - Trevor Simard
- 1CAPITAL Research Group, University of Ottawa Heart Institute, 40 Ruskin Street, H-4238, Ottawa, ON K1Y 4W7 Canada.,2Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON Canada.,3Vascular Biology and Experimental Medicine Laboratory, University of Ottawa Heart Institute, Ottawa, ON Canada.,4Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON Canada
| | - Pietro Di Santo
- 1CAPITAL Research Group, University of Ottawa Heart Institute, 40 Ruskin Street, H-4238, Ottawa, ON K1Y 4W7 Canada.,4Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON Canada
| | - Sarah Visintini
- 6Berkman Library, University of Ottawa Heart Institute, Ottawa, ON Canada
| | - Mohammad Ali Faraz
- 1CAPITAL Research Group, University of Ottawa Heart Institute, 40 Ruskin Street, H-4238, Ottawa, ON K1Y 4W7 Canada
| | - Alisha Labinaz
- 1CAPITAL Research Group, University of Ottawa Heart Institute, 40 Ruskin Street, H-4238, Ottawa, ON K1Y 4W7 Canada
| | - Young Jung
- 7Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON Canada
| | - Benjamin Hibbert
- 1CAPITAL Research Group, University of Ottawa Heart Institute, 40 Ruskin Street, H-4238, Ottawa, ON K1Y 4W7 Canada.,2Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON Canada.,3Vascular Biology and Experimental Medicine Laboratory, University of Ottawa Heart Institute, Ottawa, ON Canada.,4Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON Canada
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Michael OS, Olatunji LA. Ameliorative effect of nicotine exposure on insulin resistance is accompanied by decreased cardiac glycogen synthase kinase-3 and plasminogen activator inhibitor-1 during oral oestrogen-progestin therapy. Arch Physiol Biochem 2018; 124:139-148. [PMID: 28868937 DOI: 10.1080/13813455.2017.1369549] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
CONTEXT Cigarette smoking is considered to be a major risk factor for the development of diabetes and cardiovascular disease. Oestrogen-progestin combined oral contraceptive (COC) use has been associated with adverse cardiometabolic events. OBJECTIVE We hypothesized that nicotine would ameliorate insulin resistance (IR) that is accompanied by decreased cardiac glycogen synthase kinase-3 (GSK-3) and plasminogen activator inhibitor-1 (PAI-1). METHODS Female Wistar rats received (po) low-(0.1 mg/kg) or high-nicotine (1.0 mg/kg) with or without COC containing 5.0 µg levonorgestrel plus 1.0 µg ethinylestradiol daily for 8 weeks. RESULTS Data showed that COC treatment or nicotine exposure led to IR, glucose deregulation, atherogenic dyslipidemia, increased corticosterone, aldosterone, cardiac and circulating GSK-3 values and PAI-1. However, these effects with the exception of corticosterone and aldosterone were ameliorated in COC + nicotine-exposed rats. CONCLUSION Amelioration of IR induced by COC treatment is accompanied by decreased circulating PAI-1, cardiac PAI-1 and GSK-3 instead of circulating aldosterone and corticosterone.
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Affiliation(s)
- Olugbenga S Michael
- a Cardiovascular Research Laboratory, Department of Physiology , University of Ilorin, Ilorin, Nigeria
- b Hope Cardiometabolic Research Centre , Ilorin , Nigeria
- c Cardiometabolic Research Unit, Department of Physiology , College of Health sciences, Bowen University , Iwo , Nigeria
| | - Lawrence A Olatunji
- a Cardiovascular Research Laboratory, Department of Physiology , University of Ilorin, Ilorin, Nigeria
- b Hope Cardiometabolic Research Centre , Ilorin , Nigeria
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Becker C, Kukat A, Szczepanowska K, Hermans S, Senft K, Brandscheid CP, Maiti P, Trifunovic A. CLPP deficiency protects against metabolic syndrome but hinders adaptive thermogenesis. EMBO Rep 2018; 19:e45126. [PMID: 29588285 PMCID: PMC5934779 DOI: 10.15252/embr.201745126] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 02/26/2018] [Accepted: 02/27/2018] [Indexed: 12/21/2022] Open
Abstract
Mitochondria are fundamental for cellular metabolism as they are both a source and a target of nutrient intermediates originating from converging metabolic pathways, and their role in the regulation of systemic metabolism is increasingly recognized. Thus, maintenance of mitochondrial homeostasis is indispensable for a functional energy metabolism of the whole organism. Here, we report that loss of the mitochondrial matrix protease CLPP results in a lean phenotype with improved glucose homeostasis. Whole-body CLPP-deficient mice are protected from diet-induced obesity and insulin resistance, which was not present in mouse models with either liver- or muscle-specific depletion of CLPP However, CLPP ablation also leads to a decline in brown adipocytes function leaving mice unable to cope with a cold-induced stress due to non-functional adaptive thermogenesis. These results demonstrate a critical role for CLPP in different metabolic stress conditions such as high-fat diet feeding and cold exposure providing tools to understand pathologies with deregulated Clpp expression and novel insights into therapeutic approaches against metabolic dysfunctions linked to mitochondrial diseases.
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Affiliation(s)
- Christina Becker
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
| | - Alexandra Kukat
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
| | - Karolina Szczepanowska
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
| | - Steffen Hermans
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
| | - Katharina Senft
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
| | - Christoph Paul Brandscheid
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
| | - Priyanka Maiti
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
| | - Aleksandra Trifunovic
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
- Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
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Jung RG, Simard T, Labinaz A, Ramirez FD, Di Santo P, Motazedian P, Rochman R, Gaudet C, Faraz MA, Beanlands RS, Hibbert B. Role of plasminogen activator inhibitor-1 in coronary pathophysiology. Thromb Res 2018; 164:54-62. [DOI: 10.1016/j.thromres.2018.02.135] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 02/03/2018] [Accepted: 02/15/2018] [Indexed: 01/13/2023]
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McDowell MM, Zhao Y, Kellner CP, Barton SM, Sussman E, Claassen J, Ducruet AF, Connolly ES. Demographic and clinical predictors of multiple intracranial aneurysms in patients with subarachnoid hemorrhage. J Neurosurg 2018; 128:961-968. [DOI: 10.3171/2017.1.jns162785] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVEPathophysiological differences that underlie the development and subsequent growth of multiple aneurysms may exist. In this study, the authors assessed the factors associated with the occurrence of multiple aneurysms in patients presenting with aneurysmal subarachnoid hemorrhage (SAH).METHODSConsecutive patients presenting with aneurysmal SAH between 1996 and 2012 were prospectively enrolled in the Subarachnoid Hemorrhage Outcome Project. Patients harboring 1, 2, or 3 or more aneurysms were stratified into groups, and the clinical and radiological characteristics of each group were compared using multivariate logistic regression.RESULTSOf 1277 patients with ruptured intracranial aneurysms, 890 had 1 aneurysm, 267 had 2 aneurysms, and 120 had 3 or more aneurysms. On multinomial regression using the single-aneurysm cohort as base case, risk factors for patients presenting with 2 aneurysms were female sex (relative risk ratio [RRR] 1.80, p < 0.001), higher body mass index (BMI) (RRR 1.02, p = 0.003), more years of smoking (RRR = 1.01, p = 0.004), and black race (RRR 1.83, p = 0.001). The risk factors for patients presenting with 3 or more aneurysms were female sex (RRR 3.10, p < 0.001), higher BMI (RRR 1.03, p < 0.001), aneurysm in the posterior circulation (RRR 2.59, p < 0.001), and black race (RRR 2.15, p = 0.001). Female sex, longer smoking history, aneurysms in the posterior circulation, BMI, and black race were independently associated with the development of multiple aneurysms in our adjusted multivariate multinomial model.CONCLUSIONSSignificant demographic and clinical differences are found between patients presenting with single and multiple aneurysms in the setting of aneurysmal SAH. These predictors of multiple aneurysms likely reflect a predisposition toward inflammation and endothelial injury.
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Affiliation(s)
| | - Yin Zhao
- 1Department of Neurological Surgery, University of Pittsburgh, Pennsylvania
| | | | | | - Eric Sussman
- 3Department of Neurological Surgery, Stanford University, Stanford, California
| | - Jan Claassen
- 4Division of Neurocritical Care, Columbia University, New York, New York; and
| | - Andrew F. Ducruet
- 1Department of Neurological Surgery, University of Pittsburgh, Pennsylvania
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Relationship between plasma plasminogen activator inhibitor-1 and hypertension in American Indians: findings from the Strong Heart Study. J Hypertens 2018; 35:1787-1793. [PMID: 28379891 DOI: 10.1097/hjh.0000000000001375] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES Deficient plasminogen activator inhibitor-1 (PAI-1) prevented hypertension in mice. Plasma PAI-1 was associated with hypertension in cross-sectional analyses, but the prospective association of PAI-1 with incident hypertension in large epidemiological studies is scarce. METHODS Leveraging two longitudinal cohorts of American Indians in the Strong Heart Study (SHS, N = 1019) and the Strong Heart Family Study (SHFS, N = 1502), we examined the prospective association of plasma PAI-1 with incident hypertension by multivariate logistic regression, adjusting for age, sex, study site, smoking, drinking, dietary sodium, obesity, lipids, fasting glucose, kidney function, inflammation, and follow-up years. Family relatedness in the SHFS was accounted for using the GLIMMIX procedure. Plasma PAI-1 level at baseline was measured by immunoassay. All participants were free of hypertension, cardiovascular diseases, and chronic kidney disease at baseline. RESULTS A total of 305 and 258 participants, respectively, from the SHS (57 ± 7 years) and the SHFS (33 ± 13 years) developed incident hypertension during follow-up. In the SHS, higher level of log-transformed PAI-1 was associated with 1.35-fold increased risk of hypertension [odds ratio (OR) (95% confidence interval): 1.35 (1.06-1.72)]. Analysis using categorical PAI-1 (in tertiles) showed that participants in the highest tertile (≥58 ng/ml) had 63% increased risk for hypertension [OR = 1.63 (1.12-2.37)] compared with those in the lowest tertile (<33 ng/ml). This association was confirmed in the SHFS with similar effect sizes [OR = 1.41 (1.11-1.81) for log-transformed PAI-1; OR = 1.64 (1.08-2.50) for categorical PAI-1: ≥58 vs. <33 ng/ml]. CONCLUSION A higher level of plasma PAI-1 is significantly associated with hypertension in American Indians, independent of established risk factors. The potential causality warrants further investigation.
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Morel S, Kwak B, Rohner-Jeanrenaud F, Steffens S, Molica F. Adipokines at the crossroad between obesity and cardiovascular disease. Thromb Haemost 2017; 113:553-66. [DOI: 10.1160/th14-06-0513] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 09/18/2014] [Indexed: 12/31/2022]
Abstract
SummaryObesity, and especially excessive visceral adipose tissue accumulation, is considered as a low-grade inflammatory state that is responsible for adipocyte dysfunction and associated metabolic disorders. Adipose tissue displays endocrine functions by releasing pro- or antiinflammatory bioactive molecules named adipokines. An altered expression of these molecules, provoked by obesity or adipocyte dysregulation, contributes to major metabolic diseases such as insulin resistance and type 2 diabetes mellitus that are important risk factors for cardiovascular disease. However, obesity is also characterised by the expansion of perivascular adipose tissue that acts locally via diffusion of adipokines into the vascular wall. Local inflammation within blood vessels induced by adipokines contributes to the onset of endothelial dysfunction, atherosclerosis and thrombosis, but also to vascular remodelling and hypertension. A fast expansion of obesity is expected in the near future, which will rapidly increase the incidence of these cardiovascular diseases. The focus of this review is to summarise the link between metabolic and cardiovascular disease and discuss current treatment approaches, limitations and future perspectives for more targeted therapies.
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Svenningsen P, Hinrichs GR, Zachar R, Ydegaard R, Jensen BL. Physiology and pathophysiology of the plasminogen system in the kidney. Pflugers Arch 2017; 469:1415-1423. [DOI: 10.1007/s00424-017-2014-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 06/09/2017] [Accepted: 06/12/2017] [Indexed: 12/31/2022]
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Plasminogen Activator Inhibitor-1 is Regulated Through Dietary Fat Intake and Heritability: Studies in Twins. Twin Res Hum Genet 2017. [DOI: 10.1017/thg.2017.36] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In different pathophysiological conditions plasminogen activator inhibitor-1 (PAI-1) plasma concentrations are elevated. As dietary patterns are considered to influence PAI-1 concentration, we aimed to determine active PAI-1 plasma concentrations and mRNA expression in adipose tissue before and after consumption of a high-fat diet (HFD) and the impact of additive genetic effects herein in humans. For 6 weeks, 46 healthy, non-obese pairs of twins (aged 18–70) received a normal nutritionally balanced diet (ND) followed by an isocaloric HFD for 6 weeks. Active PAI-1 plasma levels and PAI-1 mRNA expression in subcutaneous adipose tissue were assessed after the ND and after 1 and 6 weeks of HFD. Active PAI-1 plasma concentrations and PAI-1 mRNA expression in adipose tissue were significantly increased after both 1 and 6 weeks of HFD when compared to concentrations determined after ND (p< .05), with increases of active PAI-1 being independent of gender, age, or changes of BMI and intrahepatic fat content, respectively. However, analysis of covariance suggests that serum insulin concentration significantly affected the increase of active PAI-1 plasma concentrations. Furthermore, the increase of active PAI-1 plasma concentrations after 6 weeks of HFD was highly heritable (47%). In contrast, changes in PAI-1 mRNA expression in fatty tissue in response to HFD showed no heritability and were independent of all tested covariates. In summary, our data suggest that even an isocaloric exchange of macronutrients — for example, a switch to a fat-rich diet — affects PAI-1 concentrations in humans and that this is highly heritable.
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Avogaro A. Re: "Plasminogen Activator Inhibitor-1 and Pericardial Fat in Individuals with Type 2 Diabetes Mellitus" by Bayomi et al. (Metab Syndr Relat Disord 2017;15:269-275). Metab Syndr Relat Disord 2017; 15:266-268. [PMID: 28605281 DOI: 10.1089/met.2017.0070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Plasminogen activator inhibitor-1 (PAI-1) is a member of the serine protease inhibitor (serpin) superfamily, which inactivates tissue plasminogen activator (tPA); therefore, increased level of PAI-1 antigen counteracts the anticoagulant effect of tPA and facilitates the fibrin clot formation. Plasma PAI-1 antigen and activity levels are associated with increased body mass index and with features of the insulin resistance syndrome like obesity and diabetes. Visceral adipose tissue produces more PAI-1 than subcutaneous adipose tissue: This increased production of PAI-1 from the visceral adipose tissue is one important link between visceral obesity and cardiovascular disease. Besides visceral adipose tissue, there is mounting evidence that epicardial adipose tissue may be an important source of PAI-1, especially in patients with type 2 diabetes.
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Affiliation(s)
- Angelo Avogaro
- Department of Medicine, University of Padova , School of Medicine, Padova, Italy
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Parnell JA, Klancic T, Reimer RA. Oligofructose decreases serum lipopolysaccharide and plasminogen activator inhibitor-1 in adults with overweight/obesity. Obesity (Silver Spring) 2017; 25:510-513. [PMID: 28229548 DOI: 10.1002/oby.21763] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 11/10/2016] [Accepted: 12/08/2016] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To determine the effect of prebiotic supplementation on metabolic endotoxemia and systemic inflammation in adults with overweight and obesity. METHODS Samples from a previously conducted randomized, double-blind, placebo-controlled trial were used for analysis. Participants were randomized to 21 g of oligofructose (n = 20; BMI 30.4 kg/m2 ) or a maltodextrin placebo (n = 17; BMI 29.5 kg/m2 ) for 12 weeks. A total of 37 participants had samples available for the current analysis. Resistin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage chemoattractant protein-1 (MCP-1) were quantified using MILLIPLEX® assays. Lipopolysaccharide (LPS) was measured using PyroGene™ Recombinant Factor C Assay. RESULTS Plasma LPS concentrations were reduced by 40% in the oligofructose group over 12 weeks compared to a 48% increase in the placebo group (P = 0.04). PAI-1, a risk factor for thrombosis, was reduced to a greater extent in the oligofructose group (-17.3 ± 2.6 ng/ml) compared to the placebo group (-9.7 ± 1.8 ng/ml; P = 0.03). Oligofructose did not affect IL-6, TNF-α, MCP-1, adiponectin, or resistin. CONCLUSIONS Oligofructose reduces metabolic endotoxemia and PAI-1. Incorporating prebiotics into the diet through supplements or functional foods may help mitigate some markers of obesity-associated inflammation.
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Affiliation(s)
- Jill A Parnell
- Department of Health and Physical Education, Mount Royal University, Calgary, Alberta, Canada
| | - Teja Klancic
- Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada
| | - Raylene A Reimer
- Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, Calgary, Alberta, Canada
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Kodaman N, Aldrich MC, Sobota R, Asselbergs FW, Brown NJ, Moore JH, Williams SM. Plasminogen Activator Inhibitor-1 and Diagnosis of the Metabolic Syndrome in a West African Population. J Am Heart Assoc 2016; 5:e003867. [PMID: 27697752 PMCID: PMC5121488 DOI: 10.1161/jaha.116.003867] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 09/01/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Metabolic syndrome (MetS) is diagnosed by the presence of at least 3 of the following: obesity, hypertension, hyperglycemia, hypertriglyceridemia, and low high-density lipoprotein. Individuals with MetS also typically have elevated plasma levels of the antifibrinolytic factor, plasminogen activator inhibitor-1 (PAI-1), but the relationships between PAI-1 and MetS diagnostic criteria are not clear. Understanding these relationships can elucidate the relevance of MetS to cardiovascular disease risk, because PAI-1 is associated with ischemic events and directly involved in thrombosis. METHODS AND RESULTS In a cross-sectional analysis of 2220 Ghanaian men and women from urban and rural locales, we found the age-standardized prevalence of MetS to be as high as 21.4% (urban women). PAI-1 level increased exponentially as the number of diagnostic criteria increased linearly (P<10-13), supporting the conclusion that MetS components have a joint effect that is stronger than their additive contributions. Body mass index, triglycerides, and fasting glucose were more strongly correlated with PAI-1 than with canonical MetS criteria, and this pattern did not change when pair-wise correlations were conditioned on all other risk factors, supporting an independent role for PAI-1 in MetS. Finally, whereas the correlations between conventional risk factors did not vary significantly by sex or across urban and rural environments, correlations with PAI-1 were generally stronger among urban participants. CONCLUSIONS MetS prevalence in the West African population we studied was comparable to that of the industrialized West. PAI-1 may serve as a key link between MetS, as currently defined, and the endpoints with which it is associated. Whether this association is generalizable will require follow-up.
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Affiliation(s)
- Nuri Kodaman
- Vanderbilt Genetics Institute, Vanderbilt University Medical School, Nashville, TN Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH
| | - Melinda C Aldrich
- Division of Epidemiology, Department of Thoracic Surgery, Vanderbilt University Medical School, Nashville, TN
| | - Rafal Sobota
- Vanderbilt Genetics Institute, Vanderbilt University Medical School, Nashville, TN Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH
| | - Folkert W Asselbergs
- Division of Heart & Lungs, Department of Cardiology, UMC Utrecht, Utrecht, The Netherlands Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom
| | - Nancy J Brown
- Department of Medicine, Vanderbilt University Medical School, Nashville, TN
| | - Jason H Moore
- Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH Department of Biostatistics and Epidemiology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Scott M Williams
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH
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Barnard SA, Pieters M, Nienaber-Rousseau C, Kruger HS. Degree of obesity influences the relationship of PAI-1 with body fat distribution and metabolic variables in African women. Thromb Res 2016; 146:95-102. [DOI: 10.1016/j.thromres.2016.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 08/19/2016] [Accepted: 09/06/2016] [Indexed: 11/16/2022]
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Ji Y, Weng Z, Fish P, Goyal N, Luo M, Myears SP, Strawn TL, Chandrasekar B, Wu J, Fay WP. Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation. Arterioscler Thromb Vasc Biol 2016; 36:2167-2175. [PMID: 27659097 DOI: 10.1161/atvbaha.116.308344] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 09/09/2016] [Indexed: 01/23/2023]
Abstract
OBJECTIVE Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that promotes and inhibits cell migration, plays a complex and important role in adverse vascular remodeling. Little is known about the effects of pharmacological PAI-1 inhibitors, an emerging drug class, on migration of vascular smooth muscle cells (SMCs) and endothelial cells (ECs), crucial mediators of vascular remodeling. We investigated the effects of PAI-039 (tiplaxtinin), a specific PAI-1 inhibitor, on SMC and EC migration in vitro and vascular remodeling in vivo. APPROACH AND RESULTS PAI-039 inhibited SMC migration through collagen gels, including those supplemented with vitronectin and other extracellular matrix proteins, but did not inhibit migration of PAI-1-deficient SMCs, suggesting that its antimigratory effects were PAI-1-specific and physiologically relevant. However, PAI-039 did not inhibit EC migration. PAI-039 inhibited phosphorylation and nuclear translocation of signal transducers and activators of transcription-1 in SMCs, but had no discernable effect on signal transducer and activator of transcription-1 signaling in ECs. Expression of low-density lipoprotein receptor-related protein 1, a motogenic PAI-1 receptor that activates Janus kinase/signal transducers and activators of transcription-1 signaling, was markedly lower in ECs than in SMCs. Notably, PAI-039 significantly inhibited intimal hyperplasia and inflammation in murine models of adverse vascular remodeling, but did not adversely affect re-endothelialization after endothelium-denuding mechanical vascular injury. CONCLUSIONS PAI-039 inhibits SMC migration and intimal hyperplasia, while having no inhibitory effect on ECs, which seems to be because of differences in PAI-1-dependent low-density lipoprotein receptor-related protein 1/Janus kinase/signal transducer and activator of transcription-1 signaling between SMCs and ECs. These findings suggest that PAI-1 may be an important therapeutic target in obstructive vascular diseases characterized by neointimal hyperplasia.
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Affiliation(s)
- Yan Ji
- From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO
| | - Zhen Weng
- From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO
| | - Philip Fish
- From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO
| | - Neha Goyal
- From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO
| | - Mao Luo
- From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO
| | - Samantha P Myears
- From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO
| | - Tammy L Strawn
- From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO
| | - Bysani Chandrasekar
- From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO
| | - Jianbo Wu
- From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO
| | - William P Fay
- From the Departments of Medicine and Medical Pharmacology & Physiology, University of Missouri School of Medicine (Y.J., Z.W., P.F., N.G., M.L., S.P.M., T.L.S., B.C., J.W., W.P.F.), and the Research Service, Harry S. Truman Memorial Veterans Hospital (B.C., W.P.F.), Columbia, MO.
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Eddy JL, Schroeder JA, Zimbler DL, Caulfield AJ, Lathem WW. Proteolysis of plasminogen activator inhibitor-1 by Yersinia pestis remodulates the host environment to promote virulence. J Thromb Haemost 2016; 14:1833-43. [PMID: 27377187 PMCID: PMC5053288 DOI: 10.1111/jth.13408] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 05/27/2016] [Indexed: 01/23/2023]
Abstract
UNLABELLED Essentials Effect of plasminogen activator inhibitor (PAI)-1 on plague and its Y. pestis cleavage is unknown. An intranasal mouse model of infection was used to determine the role of PAI-1 in pneumonic plague. PAI-1 is cleaved and inactivated by the Pla protease of Y. pestis in the lung airspace. PAI-1 impacts both bacterial outgrowth and the immune response to respiratory Y. pestis infection. Click to hear Dr Bock discuss pathogen activators of plasminogen. SUMMARY Background The hemostatic regulator plasminogen activator inhibitor-1 (PAI-1) inactivates endogenous plasminogen activators and aids in the immune response to bacterial infection. Yersinia pestis, the causative agent of plague, produces the Pla protease, a virulence factor that is required during plague. However, the specific hemostatic proteins cleaved by Pla in vivo that contribute to pathogenesis have not yet been fully elucidated. Objectives To determine whether PAI-1 is cleaved by the Pla protease during pneumonic plague, and to define the impact of PAI-1 on Y. pestis respiratory infection in the presence or absence of Pla. Methods An intranasal mouse model of pneumonic plague was used to assess the levels of total and active PAI-1 in the lung airspace, and the impact of PAI-1 deficiency on bacterial pathogenesis, the host immune response and plasmin generation following infection with wild-type or ∆pla Y. pestis. Results We found that Y. pestis cleaves and inactivates PAI-1 in the lungs in a Pla-dependent manner. The loss of PAI-1 enhances Y. pestis outgrowth in the absence of Pla, and is associated with increased conversion of plasminogen to plasmin. Furthermore, we found that PAI-1 regulates immune cell recruitment, cytokine production and tissue permeability during pneumonic plague. Conclusions Our data demonstrate that PAI-1 is an in vivo target of the Pla protease in the lungs, and that PAI-1 is a key regulator of the pulmonary innate immune response. We conclude that the inactivation of PAI-1 by Y. pestis alters the host environment to promote virulence during pneumonic plague.
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Affiliation(s)
- J L Eddy
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - J A Schroeder
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - D L Zimbler
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - A J Caulfield
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - W W Lathem
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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Bucci JC, Trelle MB, McClintock CS, Qureshi T, Jørgensen TJD, Peterson CB. Copper(II) Ions Increase Plasminogen Activator Inhibitor Type 1 Dynamics in Key Structural Regions That Govern Stability. Biochemistry 2016; 55:4386-98. [DOI: 10.1021/acs.biochem.6b00256] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Joel C. Bucci
- Department
of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Walters Life Sciences Building, 1414 Cumberland Avenue, Knoxville, Tennessee 37996, United States
- Department
of Biological Sciences, Louisiana State University, A221 Life
Sciences Annex, Baton Rouge, Louisiana 70803, United States
| | - Morten Beck Trelle
- Department
of Biochemistry and Molecular Biology, University of Southern Denmark, 55 Campusvej, 5000 Odense M, Denmark
| | - Carlee S. McClintock
- Department
of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Walters Life Sciences Building, 1414 Cumberland Avenue, Knoxville, Tennessee 37996, United States
| | - Tihami Qureshi
- Department
of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Walters Life Sciences Building, 1414 Cumberland Avenue, Knoxville, Tennessee 37996, United States
| | - Thomas J. D. Jørgensen
- Department
of Biochemistry and Molecular Biology, University of Southern Denmark, 55 Campusvej, 5000 Odense M, Denmark
| | - Cynthia B. Peterson
- Department
of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Walters Life Sciences Building, 1414 Cumberland Avenue, Knoxville, Tennessee 37996, United States
- Department
of Biological Sciences, Louisiana State University, A221 Life
Sciences Annex, Baton Rouge, Louisiana 70803, United States
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Barnard SA, Pieters M, De Lange Z. The contribution of different adipose tissue depots to plasma plasminogen activator inhibitor-1 (PAI-1) levels. Blood Rev 2016; 30:421-429. [PMID: 27233154 DOI: 10.1016/j.blre.2016.05.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 04/15/2016] [Accepted: 05/13/2016] [Indexed: 12/31/2022]
Abstract
Increased plasma plasminogen activator inhibitor-1 (PAI-1) level is considered a mechanistic pathway through which obesity contributes to increased cardiovascular disease risk. Abdominal adipose tissue specifically, is a major PAI-1 source with visceral adipose tissue (VAT), an ectopic fat depot, generally considered to produce more PAI-1 than subcutaneous adipose tissue. However, this does not necessarily lead to increased plasma PAI-1 levels. This review provides an overview of studies investigating the association between body fat distribution and plasma PAI-1 levels. It discusses factors that influence this relationship and also considers the contribution of other tissue to plasma PAI-1 levels, placing the relative contribution of adipose tissue into perspective. In conclusion, the relationship between VAT and plasma PAI-1 levels is not fixed but can be modulated by a number of factors such as the size of the subcutaneous adipose tissue depot, ethnicity, possibly genetics and other obesity-related metabolic abnormalities.
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Affiliation(s)
- Sunelle A Barnard
- Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa.
| | - Marlien Pieters
- Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa.
| | - Zelda De Lange
- Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa.
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Blood coagulation and metabolic profiles in middle-aged male and female ob/ob mice. Blood Coagul Fibrinolysis 2016; 26:522-6. [PMID: 25692523 DOI: 10.1097/mbc.0000000000000267] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Obese and diabetic states in humans are associated with an increased incidence of thrombotic diseases caused by various coagulation abnormalities. Genetically obese ob/ob mice produce metabolic abnormalities similar to those associated with type 2 diabetes. However, little is known about their coagulation features or sex differences. The present study aimed to determine the effects of obese and diabetic complications on blood coagulation and vascular diseases by exploring correlations between blood coagulation and metabolic profiles in middle-aged male and female ob/ob mice. Plasma levels of plasminogen activator inhibitor 1 (PAI-1) were significantly increased, whereas those that of platelet factor-4 (PF-4) was slightly, but significantly increased in male and female ob/ob mice compared with lean counterparts. Prothrombin time (PT) was significantly shortened in female ob/ob mice and activated partial thrombin time (APTT) significantly differed between male and female ob/ob mice. Plasma levels of antithrombin (AT) were significantly increased in male and female ob/ob mice. None of the other coagulation and fibrinolytic factors examined significantly differed between ob/ob mice and lean counterparts. On the contrary, factors such as body weight and cholesterol levels significantly differed between ob/ob and lean mice, whereas glucose, fructosamine and insulin levels significantly differed only in one sex of each strain. These results provided fundamental information about blood coagulation and metabolic features for exploring the function of altered blood coagulation states in ob/ob mice.
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