Regulatory role of NADPH oxidase in glycated LDL-induced upregulation of plasminogen activator inhibitor-1 and heat shock factor-1 in mouse embryo fibroblasts and diabetic mice |
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| Affiliation: | 1. Department of Internal Medicine, University of Manitoba, Winnipeg, Canada MB R3E 3P4;2. Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Canada MB R3E 3P4;1. Medical College, Qingdao University, Qingdao, 266071, China;2. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China;3. Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical College, Zunyi, 563003, China;4. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China;1. Hope Institute Hospital, Kingston, Jamaica;2. Faculty of Medicine, University of the West Indies, Kingston, Jamaica;3. Jamaica Cancer Care and Research Institute, University of the West Indies, Kingston, Jamaica;4. Department of Pathology, University of the West Indies, Kingston, Jamaica;5. Harvard/ MGH Center on Genomics, Vulnerable Populations, and Health Disparities, Mongan Institute, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA;6. School of Anthropology and Museum Ethnography, University of Oxford, Oxford, UK;7. Caribbean Public Health Agency, Port of Spain, Trinidad and Tobago;8. Division of Public Health Sciences, Fred Hutchinson Cancer Research Institute, Seattle, WA, USA;9. Faculty of Medical Sciences, The University of the West Indies, Saint Augustine, Trinidad and Tobago;10. Cancer Surveillance Section, International Agency for Research on Cancer, Lyon, France;11. Global Initiative for Cancer Registry Development, International Agency for Research on Cancer, Lyon, France;12. Oncology Unit, Dr Robert Reid Cabral Children''s Hospital, Santo Domingo, Dominican Republic;13. Faculty of Medical Sciences, University of the West Indies, Wanstead, Barbados;14. Division of Haematology/ Oncology, Hospital for Sick Children, Faculty of Medicine and IHPME, University of Toronto, Toronto, ON, Canada;15. Cayman Hospice Care, George Town, Cayman Islands;p. The Caribbean Association for Oncology and Hematology, Port of Spain, Trinidad and Tobago;q. University of West Indies School of Nursing, Saint Augustine, Trinidad and Tobago;r. Princess Margaret Hospital, Nassau, The Bahamas;s. Cancer Control and Population Sciences, University of Puerto Rico Comprehensive Cancer Centre, San Juan, Puerto Rico;t. Department of Medicine, Harvard Medical School, Boston, MA, USA;1. Department of Orthopaedic Surgery & Rehabilitation, William Beaumont Army Medical Center/Texas Tech University Health Science Center, El Paso, TX, USA;2. Department of Orthopaedic Surgery, John A. Feagin Jr. Sports Medicine Fellowship, Keller Army Hospital, West Point, NY, USA;3. Department of Orthopaedics and Rehabilitation, Fort Belvoir Community Hospital, Fort Belvoir, VA, USA;4. US Special Operations Command, MacDill Air Force Base, Tampa, FL, USA;5. Department of Orthopaedics and Rehabilitation, Yale Medical School/Yale New Haven Hospital, New Haven, CT, USA;1. Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuan Jiagang, Yuzhong District, Chongqing 400016, China;2. Laboratory of Lipid and Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China |
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| Abstract: | Cardiovascular disease is the predominant cause of death in diabetic patients. Fibroblasts are one of the major types of cells in the heart or vascular wall. Increased levels of glycated low-density lipoprotein (glyLDL) were detected in diabetic patients. Previous studies in our group demonstrated that oxidized LDL increased the amounts of NADPH oxidase (NOX), plasminogen activator inhibitor-1 (PAI-1), and heat shock factor-1 (HSF1) in fibroblasts. This study examined the expression of NOX, PAI-1, and HSF1 in glyLDL-treated wild-type or HSF1-deficient mouse embryo fibroblasts (MEFs) and in leptin receptor-knockout (db/db) diabetic mice. Treatment with physiologically relevant levels of glyLDL increased superoxide and H2O2 release and the levels of NOX4 and p22phox (an essential component of multiple NOX complexes) in wild-type or HSF1-deficient MEFs. The levels of HSF1 and PAI-1 were increased by glyLDL in wild-type MEFs, but not in HSF1-deficient MEFs. Diphenyleneiodonium (a nonspecific NOX inhibitor) or small interfering RNA for p22phox prevented glyLDL-induced increases in the levels of NOX4, HSF1, or PAI-1 in MEFs. The amounts of NOX4, HSF1, and PAI-1 were elevated in hearts of db/db diabetic mice compared to wild-type mice. The results suggest that glyLDL increased the abundance of NOX4 or p22phox via an HSF1-independent pathway, but that of PAI-1 via an HSF1-dependent manner. NOX4 plays a crucial role in glyLDL-induced expression of HSF1 and PAI-1 in mouse fibroblasts. Increased expression of NOX4, HSF1, and PAI-1 was detected in cardiovascular tissue of diabetic mice. |
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| Keywords: | NADPH oxidase Glycated low-density lipoprotein Plasminogen activator inhibitor-1 Heat shock factor-1 Mouse embryo fibroblasts Leptin receptor-knockout diabetic mice Free radicals |
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