Oxidized LDL activates PAI-1 transcription through autocrine activation of TGF-β signaling in mesangial cells

Song, Chi Young; Kim, Bong Cho; Hong, Hye Kyoung; Lee, Hyun Soon

doi:10.1111/j.1523-1755.2005.00271.x

Cited by 37 publications

(34 citation statements)

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“…PAI-1 may also play a critical role in the development of agingassociated pathological changes associated with CAD (Yamamoto et al 2014). Early work has indicated that PAI-1 can be upregulated through oxidative stress (Vulin and Stanley 2004) and inflammation (Alessi and Juhan-Vague 2004;Song et al 2005). Hence, significant inhibition of PAI-1 by F105 supplementation would be of benefit in attenuating the deterioration of vessels particularly in a subset of subjects with initial HbA1c > 5.4 and one additional cardiometabolic risk factor.…”

Section: Discussionmentioning

confidence: 99%

Synergistic in vitro antioxidant activity and observational clinical trial of F105, a phytochemical formulation includingCitrus bergamia, in subjects with moderate cardiometabolic risk factors

Babish¹,

Dahlberg

et al. 2016

Can. J. Physiol. Pharmacol.

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Abstract:We examined the clinical safety and efficacy of F105 in 11 subjects with moderate dyslipidemia. F105 is a combination of bergamot fruit extract (Citrus bergamia, BFE) and 9 phytoextracts selected for their ability to improve the antioxidant and anti-inflammatory activity of BFE. In vitro F105 exhibited a synergistic inhibition of oxygen radical absorbing capacity, peroxynitrite formation, and myeloperoxidase activity. Following 12 weeks of F105 daily, no treatment-related adverse events or changes in body mass were seen. Statistically significant changes were noted in total cholesterol (−7.3%), LDL-cholesterol (−10%), non-HDL cholesterol (−7.1%), cholesterol/HDL (−26%), and apolipoprotein B (−2.8%). A post hoc analysis of 8 subjects with HbA1c > 5.4 and HOMA-IR score > 2 or elevated triglycerides revealed additional statistically significant changes in addition to those previously observed in all subjects including triglycerides (−27%), oxLDL (−19%), LDL/HDL (−25%), triglycerides/HDL (−27%), oxLDL/HDL (−25%), and PAI-1 (−37%). A follow-up case report of a 70-year-old female patient, nonresponsive to statin therapy and placed on F105 daily, demonstrated improved cardiometabolic variables over 12 weeks similar to the subgroup. In summary, F105 was clinically well-tolerated and effective for ameliorating dyslipidemia in subjects with moderate cardiometabolic risk factors, particularly in the individuals with HbA1c > 5.4%.Key words: cardiometabolic disease, bergamot, antioxidant, myeloperoxidase, oxidized LDL, dyslipidemia, HbA1c. Résumé :Les auteurs ont examiné la sécurité et l'efficacité cliniques du F105 chez 11 sujets présentant une dyslipidémie modérée. Le F105 est une combinaison d'extrait de bergamote (Citrus bergamia, EB) et 9 extraits végétaux sélectionnés pour leur capacité à améliorer l'activité antioxydante et anti-inflammatoire de l'EB. In vitro, le F105 montrait une inhibition synergique de la capacité d'absorption des radicaux d'oxygène, de formation de peroxynitrite et de l'activité myéloperoxydase. Après 12 semaines d'administration quotidienne de F105, aucun effet secondaire indésirable relié au traitement ou changements de poids corporels n'étaient observés. Des changements statistiquement significatifs ont été notés quant au cholestérol total (−7,3 %), LDL-cholestérol (−10 %), non-HDL-cholestérol (−7,1 %), cholestérol/HDL (−26 %) et apolipoprotéine B (−2,8 %). Une analyse post hoc de 8 sujets présentant une HbA1c > 5.4 et un indice HOMA-IR >2 ou des triglycérides élevés a révélé des changements additionnels statistiquement significatifs en plus de ceux précédemment observés chez tous les sujets incluant les triglycérides (−27 %), oxLDL (−19 %), LDL/HDL (−25 %) triglycérides/HDL (−27 %), oxLDL/HDL (−25 %), et PAI-1 (−37 %). Une étude de cas de suivi d'une patiente de 70 ans, ne répondant pas à la thérapie par les statines et traitée au F105 quotidiennement, a démontré amélioration des variables cardiométaboliques pendant les 12 semaines similaire au sous-groupe. En résumé, le F105 est bie...

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Section: Discussionmentioning

confidence: 99%

Synergistic in vitro antioxidant activity and observational clinical trial of F105, a phytochemical formulation includingCitrus bergamia, in subjects with moderate cardiometabolic risk factors

Babish¹,

Dahlberg

et al. 2016

Can. J. Physiol. Pharmacol.

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“…Oxidized LDL has been shown to stimulate the secretion of excess extracellular matrix, MCP-1 and PAI-1 from mesangial cells (92,126,127). These effects may be related to binding of these lipoproteins to VLDL and LDL receptors in mesangial cells (92,126).…”

Section: Role Of Tg-rich Lipoproteinsmentioning

confidence: 99%

Obesity and Obesity-Initiated Metabolic Syndrome

Wahba

Mak

2007

Clinical Journal of the American Society of Nephrology

460

343

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There is an epidemic of obesity and the metabolic syndrome in the United States and across the world. Both entities are associated with high mortality, mainly as a result of cardiovascular disease. The epidemic of obesity has been paralleled by an increase in the incidence of chronic kidney disease (CKD). Several recent epidemiologic studies have shown that obesity and the metabolic syndrome are independent predictors of CKD. In addition to diabetes and hypertension, several other mechanisms have been postulated to initiate and maintain kidney injury in patients with obesity and the metabolic syndrome. This article reviews the recent epidemiologic data linking obesity and the metabolic syndrome to CKD and summarizes the potential mechanisms of renal injury in this setting, with a focus on the role of inflammation, lipotoxicity, and hemodynamic factors. Potential preventive and therapeutic modalities based on the limited evidence available are discussed.Clin , and the increase occurred for both men and women and for all age groups (2). Since then, the trend for increased prevalence has continued, particularly for adolescents and men (1). Obesity is also on the rise in other industrialized countries (3-5). The metabolic syndrome, previously known as syndrome X and a major consequence of obesity, is also on the rise (6). According to the Third National Health and Nutrition Examination Survey (NHANES III), the prevalence of the metabolic syndrome in the United States is 23% in those who are 20 yr or older and Ͼ40% in those who are 60 yr or older (7). According to the Third Adult Treatment Panel of the National Cholesterol Education Program, the metabolic syndrome is defined as the presence of at least three of the following criteria, with or without diabetes: Central obesity (waist circumference in men Ͼ102 cm and in women Ͼ88 cm), hypertriglyceridemia (Ն150 mg/dl), low HDL cholesterol (men Ͻ40 mg/dl, women Ͻ50 mg/dl), elevated fasting glucose (Ͼ110 mg/dl), and hypertension (Ն130/85 mmHg) (8). A central feature of the metabolic syndrome is insulin resistance, which results in hyperglycemia and hyperinsulinemia, and eventually leads to the development of diabetes (9). Central obesity is the most important predisposing factor for insulin resistance (9). Chronic inflammation is another feature of the metabolic syndrome, which, together with insulin resistance, results in complex metabolic derangements that contribute to the pathogenesis of hypertension, lipoprotein abnormalities, atherosclerosis, coronary artery disease, and other organ dysfunction (10,11). Both obesity and the metabolic syndrome are associated with high mortality, mainly related to cardiovascular disease (12,13). Overweight, obesity, and the metabolic syndrome have recently emerged as strong independent risk factors for chronic kidney disease (CKD) and ESRD. This article reviews the epidemiology of CKD in relationship to obesity and the metabolic syndrome and the possible mechanisms of renal injury that is caused by obesity and obesity-initiated metab...

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“…LDL, and especially oxidised LDL, may increase the levels of several cytokines in renal vasculature and tissues, thus contributing to monocyte infiltration into the mesangial space, mesangial cell hypercellularity, and mesangial extracellular matrix deposition [18][19][20]. Moreover, the increased cytokine production might disturb podocyteendothelial cell communication, causing glomerular endothelial cell dysfunction and leading to microalbuminuria [21].…”

Section: Introductionmentioning

confidence: 99%

Effects of different LDL particles on inflammatory molecules in human mesangial cells

et al. 2008

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Aims/hypothesis Inflammation is a mechanism of glomerular damage in chronic glomerulopathies. LDL may increase the production of inflammatory cytokines in renal tissues. However, the relative role of native, oxidised and glycated LDL in promoting this process has been only partially elucidated. Methods We tested the inflammatory and proapoptotic effects of native, oxidised and glycated LDL in human mesangial cells (HMCs) by measuring levels of IL6, CD40 and macrophage migration inhibitory factor (MIF) genes, MIF protein, release of IL6, soluble CD40, fibronectin and laminin, early and late apoptosis, and extracellular regulated kinases (ERK) 1/2 and c-Jun N-terminal kinase (JNK) activation. Results IL6 and CD40 mRNA were dose-dependently upregulated by all three species; this was closely paralleled by their increased release. MIF mRNA was potently stimulated by modified LDL, as confirmed by immunostaining. Fibronectin and laminin release was stimulated by both oxidised and glycated, but not native, LDL. All LDL species induced some increase in late, but not early, apoptosis, and similarly activated JNK2/3 phosphorylation; in contrast, ERK1/2 phosphorylation was more strongly upregulated by oxidised than either native or glycated LDL.Conclusions In HMCs, the production and release of IL6 and CD40 is stimulated by both native and modified LDL, while MIF is more strongly stimulated by oxidised LDL. Regarding the pattern of mesangial expansion, fibronectin and laminin are upregulated by oxidised and glycated LDL. Apoptosis, if modest, is induced by all species. Intracellular signalling of native and modified LDL involves JNK2/3 and, perhaps more specifically, ERK1/2. Tight control of the lipid profile may be useful in preserving kidney function in patients with metabolic alterations.

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Oxidized LDL activates PAI-1 transcription through autocrine activation of TGF-β signaling in mesangial cells

Cited by 37 publications

References 36 publications

Synergistic in vitro antioxidant activity and observational clinical trial of F105, a phytochemical formulation includingCitrus bergamia, in subjects with moderate cardiometabolic risk factors

Synergistic in vitro antioxidant activity and observational clinical trial of F105, a phytochemical formulation includingCitrus bergamia, in subjects with moderate cardiometabolic risk factors

Obesity and Obesity-Initiated Metabolic Syndrome

Effects of different LDL particles on inflammatory molecules in human mesangial cells

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