Higher Plasma Thrombospondin-1 Levels in Patients With Coronary Artery Disease and Diabetes Mellitus

Choi, Kyung-Chul; Kim, Dong‐Bin; Kim, Myung-Jun; Kwon, Bum-June; Chang, Seo-Yoon; Jang, Sung-Won; Cho, Eun-Joo; Rho, Tai-Ho; Kim, Jae-Hyung

doi:10.4070/kcj.2012.42.2.100

Cited by 42 publications

(32 citation statements)

References 27 publications

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“…Although the blood sampling and sample processing was consistent across all subjects and both centers, it is possible that some platelet activation occurred, which can result in elevated concentrations (16). However, the current results are comparable to the plasma concentrations reported in other recent studies using an ELISA in healthy individuals (30) and lower than people with ischemic heart disease and diabetes (18). The number of patients with Cushing's syndrome is small and the group is heterogeneous, containing a patient with adrenocortical carcinoma and a patient with cyclical Cushing's disease.…”

Section: Discussioncontrasting

confidence: 47%

“…As all of these actions of TSP1 are also effects of glucocorticoids (8), we hypothesize that TSP1 may be an effector of glucocorticoid activity. TSP1 has been shown to be elevated in patients with peripheral vascular disease (30) and in patients with diabetes and coronary artery disease (18). This raises the question as to whether elevated TSP1 might be a risk factor for cardiovascular disease (31), which is the leading cause of morbidity and mortality in patients with endogenous or exogenous glucocorticoid excess (6,7,32,33,34,35).…”

Section: Discussionmentioning

confidence: 99%

“…TSP1 is readily measurable in human plasma and has a half-life of 9 h (16). Plasma TSP1 is unaffected by age, sex, BMI or commonly administered medications used for the treatment of diabetes, hypertension or hyperlipidemia (16,17,18). Previous studies have indicated that TSP1 mRNA is strongly inducible by glucocorticoids in vitro (19).…”

Section: Introductionmentioning

confidence: 99%

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Thrombospondin-1 is a glucocorticoid responsive protein in humans

Barclay

Petersons

Keshvari

et al. 2016

European Journal of Endocrinology

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Objective: Thrombospondin-1 (TSP1) is a matricellular protein whose gene expression has previously been shown to increase acutely after exposure to dexamethasone in vitro. The aim of this study was to determine if TSP1 is altered by acute and chronic states of glucocorticoid excess in human subjects. Design and methods: Three studies have been undertaken to assess the difference or change in TSP1 in response to altered glucocorticoid activity: i) an acute interventional study assessed the effects of a single 4 mg dose of dexamethasone in 20 healthy volunteers; ii) a cross-sectional study compared plasma TSP1 in 20 healthy volunteers and eight patients with Cushing's syndrome; iii) an interventional study assessed the effect on plasma TSP1 of an increase in hydrocortisone dose from %20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency. Results: In healthy volunteers, 4 mg dexamethasone significantly increased peripheral blood mononuclear cell (PBMC) TSP1 mRNA levels (P!0.0001) and plasma TSP1 concentrations (P!0.0001), peaking at 12 h. Median (interquartile range) plasma TSP1 was higher in Cushing's, 638 (535-756) ng/ml, than in healthy volunteers, 272 (237-336) ng/ml (P!0.0001). Plasma TSP1 O400 ng/ml diagnosed Cushing's syndrome with sensitivity of 100% and specificity of 85%. The higher hydrocortisone dose increased plasma TSP1 from 139 (86-199) to 256 (133-516) ng/ml, (P!0.01) in patients with secondary adrenal insufficiency. Conclusions: TSP1 is a glucocorticoid responsive protein in humans. Further research is required to determine if plasma TSP1 has a role as a glucocorticoid biomarker.

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Section: Discussioncontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

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Thrombospondin-1 is a glucocorticoid responsive protein in humans

Barclay

Petersons

Keshvari

et al. 2016

European Journal of Endocrinology

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“…Likewise, plasma TSP1 levels, quantified by an aptamerbased assay, were increased in ST-elevation myocardial infarction subjects with high atherosclerotic plaque burden than in healthy controls (100). Elevated plasma TSP1 levels were independently associated with coronary artery disease in a diabetic population (30). This finding is not unexpected given data showing that TSP1 is upregulated by glucose (151,195,201,292) and increased in individuals with diabetesassociated renal disease (75).…”

Section: A Redox Signaling In Stem Cellssupporting

confidence: 48%

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

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Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

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“…Higher levels of TSP-1 have been observed in large blood vessels with atherosclerotic lesions [34], and elevated plasma levels of TSP-1 are also positively associated with coronary artery disease and diabetic mellitus [35]. A recent report demonstrated that fluvastatin, a HMG-CoA reductase inhibitor, inhibited the TGF-β 1 -induced expression of TSP-1 through the p38 MAPK pathway in human coronary artery smooth muscle cells [36].…”

Section: Discussionmentioning

confidence: 99%

Ligand-Activated Peroxisome Proliferator-Activated Receptor δ Attenuates Vascular Oxidative Stress by Inhibiting Thrombospondin-1 Expression

et al. 2018

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Thrombospondin-1 (TSP-1) is implicated in vascular diseases associated with oxidative stress, such as abdominal aortic aneurysms, ischemia-reperfusion injury, and atherosclerosis. However, the regulatory mechanisms underlying TSP-1 expression are not fully elucidated. In this study, we found that peroxisome proliferator-activated receptor δ (PPARδ) inhibited oxidative stress-induced TSP-1 expression and migration in vascular smooth muscle cells (VSMCs). Activation of PPARδ by GW501516, a specific ligand for PPARδ, significantly attenuated hydrogen peroxide (H₂O₂)-induced expression of TSP-1 in VSMCs. Small interfering RNA-mediated knockdown of PPARδ and treatment with GSK0660, a selective PPARδ antagonist, reversed the effect of GW501516 on H₂O₂-induced expression of TSP-1, suggesting that PPARδ is associated with GW501516 activity. Furthermore, JNK (c-Jun N-terminal kinase), but not p38 and ERK (extracellular signal-regulated kinase), mediated PPARδ-dependent inhibition of TSP-1 expression in VSMCs exposed to H₂O₂. GW501516- activated PPARδ also reduced the H₂O₂-induced generation of reactive oxygen species, concomitant with inhibition of VSMC migration. In particular, TSP-1 contributed to the action of PPARδ in the regulation of H₂O₂-induced interleukin-1β expression. These results suggest that PPARδ-modulated downregulation of TSP-1 is associated with reduced cellular oxidative stress, thereby inhibiting H₂O₂-induced phenotypic changes in vascular cells.

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Higher Plasma Thrombospondin-1 Levels in Patients With Coronary Artery Disease and Diabetes Mellitus

Cited by 42 publications

References 27 publications

Thrombospondin-1 is a glucocorticoid responsive protein in humans

Thrombospondin-1 is a glucocorticoid responsive protein in humans

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Ligand-Activated Peroxisome Proliferator-Activated Receptor δ Attenuates Vascular Oxidative Stress by Inhibiting Thrombospondin-1 Expression

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