Hypoxia Stimulates Osteopontin Expression and Proliferation of Cultured Vascular Smooth Muscle Cells

Sodhi, Chhinder P.; Phadke, Sarojini A.; Batlle, Daniel; Sahai, Atul

doi:10.2337/diabetes.50.6.1482

Cited by 91 publications

(84 citation statements)

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“…Hence, increased p38 MAPK activation may be involved in the development of insulin resistance and diabetes. Our findings implicate p38 MAPK in the regulation of PPARα activity and sequential OPN expression [41] . Traditionally, inflammatory cells are considered a major source of serum OPN in cases of morbid obesity [9,42] .…”

Section: Discussionsupporting

confidence: 51%

Wogonin suppresses osteopontin expression in adipocytes by activating PPARα

Zhang

Tang

et al. 2015

Acta Pharmacol Sin

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Aim: Wogonin (5,7-dihydroxy-8-methoxyflavone), a major bioactive compound of the flavonoid family, is commonly extracted from the traditional Chinese medicine Scutellaria baicalensis and possesses antioxidant and anti-inflammatory activities and is assumed to have anti-diabetes function. Indeed, a current study has shown that it can possibly treat metabolic disorders such as those found in db/db mice. However, the underlying molecular mechanism remains largely unclear. The aim of this study was to investigate the impact of wogonin on osteopontin (OPN) expression in adipose tissue from type 1 diabetic mice and in 3T3-L1 adipocytes. Methods: Type 1 diabetes was induced by streptozotocin (STZ) injection. 3T3-L1 preadipocytes were converted to 3T3-L1 adipocytes through treatment with insulin, dexamethasone, and 3-isobutyl-1-methylxanthine (IBMX). Western blot analysis and RT-PCR were performed to detect protein expression and mRNA levels, respectively. Results: Wogonin treatment suppressed the increase in serum OPN levels and reduced OPN expression in adipose tissue from STZinduced type 1 diabetic mice. Administration of wogonin enhanced PPARα expression and activity. Silencing of PPARα diminished the inhibitory effects of wogonin on OPN expression in 3T3-L1 adipocytes. Furthermore, the levels of c-Fos and phosphorylated c-Jun were reduced in wogonin-treated adipose tissue and 3T3-L1 adipocytes. In addition, wogonin treatment dramatically mitigated p38 MAPK phosphorylation. Pharmacological inhibition of p38 MAPK by its specific inhibitor SB203580 increased PPARα activity and decreased OPN expression. Conclusion: Our results suggest that wogonin downregulated OPN expression in adipocytes through the inhibition of p38 MAPK and the sequential activation of the PPARα pathway. Given the adverse effects of high OPN levels on metabolism, our results provide evidence for the potential administration of wogonin as a treatment for diabetes.

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Section: Discussionsupporting

confidence: 51%

Wogonin suppresses osteopontin expression in adipocytes by activating PPARα

Zhang

Tang

et al. 2015

Acta Pharmacol Sin

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“…It is possible that OPN synthesized by biliary epithelium in biliary atresia is acting in an autocrine fashion to maintain proliferation and/or reduce apoptosis in opposition to TNF-␣ produced by local inflammation. Consistent with this notion, OPN has been shown to mediate the proliferation of cultured mesangial and vascular smooth muscle cells (23,24,27). There is reasonable evidence to suggest that OPN and TNF-␣ may have somewhat oppositional effects in the Th1 inflammatory process.…”

Section: Discussionmentioning

confidence: 79%

“…It is involved in macrophage recruitment during inflammation, acts as a survival or mitogenic factor for epithelial and vascular cells, and is associated with extracellular matrix synthesis and fibrosis (17,19 -24). It is involved in the pathogenesis of a variety of inflammatory and fibrotic diseases including renal tubulointerstitial injury and atherosclerosis (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Most germane to this work is its role as a Th1 cytokine (33,34).…”

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confidence: 99%

Expression of Osteopontin Correlates with Portal Biliary Proliferation and Fibrosis in Biliary Atresia

et al. 2005

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The acquired or perinatal form of biliary atresia is a Th1 fibro-inflammatory disease affecting both the extrahepatic and intrahepatic bile ducts. Osteopontin (OPN) is a Th1 cytokine implicated in several fibro-inflammatory and autoimmune diseases. We examined the expression of OPN in acquired biliary atresia in comparison to normal liver and several pediatric cholestatic liver diseases. We also assessed OPN expression by cultured human bile duct epithelial cells. We found that liver OPN mRNA and protein expression were significantly increased in biliary atresia versus normal and other cholestatic diseases. OPN expression in biliary atresia was localized to epithelium of proliferating biliary structures (ductules and/or ducts) and bile plugs contained therein. No portal biliary OPN expression could be demonstrated in normal liver, syndromic biliary atresia, biliary obstruction not due to biliary atresia, and idiopathic neonatal hepatitis. OPN expression by human bile duct epithelial cells in culture was responsive to IL-2 and TNF-␣. Our results demonstrate an up-regulation of OPN expression by interlobular biliary epithelium in biliary atresia, which correlates with biliary proliferation and portal fibrosis. These findings suggest a role for OPN in the pathogenesis of biliary atresia. Biliary atresia is the most common liver disease of infancy that leads to cirrhosis, end-stage liver disease and the need for liver transplantation (1). A small proportion of cases are thought to be congenital in that they are associated with other developmental anomalies, whereas most cases are diagnosed at 4 -8 wk of age and appear to represent a disease acquired in perinatal or neonatal life. The etiology and pathogenesis of biliary atresia remain unknown. A current working unifying hypothesis that can explain the clinical and pathologic features of the acquired form of biliary atresia is that some injury to the bile ducts, likely a perinatal viral infection, leads to an autonomous immune response that results in progressive bile duct injury and fibrosis (2). This progressive, inflammatory cholangiopathy results in extrahepatic bile duct obstruction (1,3). The extrahepatic bile duct is partially or entirely obliterated by fibrosis in association with inflammation within the fibrous remnant. The intrahepatic biliary system also appears to be affected by the primary disease process. Portal areas are expanded with fibrosis and exhibit marked proliferation of biliary elements (ductules and/or ducts) (4 -8). These duct structures often contain bile plugs. Biliary proliferation may still be a feature of the disease even at end-stage, but in some cases all duct structures disappear.Previous studies have shown that the mononuclear inflammatory infiltrate in the portal tracts comprises macrophages, CD4ϩ T-cells and NK cells (9 -13). We have shown that the inflammation is typically Th1 in character, in that it consists mainly of macrophages, CD4ϩ T-cells and CD8 ϩ T-cells with production of IL-2, IFN-␥, . The inciting agent leading to thi...

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“…Many factors that facilitate atherosclerosis, such as hypoxia, high plasma glucose, 27 platelet-derived growth factor, 28 AII, 18,29 aldosterone 8 and mechanical stress, 30 also induce OPN expression. OPN has several effects that may facilitate the development and progression of cardiovascular lesions, including cell adhesion, migration, proliferation, angiogenesis and ectopic mineralization.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II receptor blockade with valsartan decreases plasma osteopontin levels in patients with essential hypertension

et al. 2010

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Osteopontin (OPN) has recently emerged as a key factor in both vascular remodelling and development of atherosclerosis. It has been reported that OPN is regulated by the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to clarify the effect of angiotensin II receptor blockade with valsartan on plasma OPN levels in patients with essential hypertension (EHT). Forty-six patients (mean age, 64 ± 11 years) with EHT were randomly assigned to treatment with amlodipine or valsartan. There were no significant differences in baseline clinical characteristics between the two groups. Blood sampling and blood pressure evaluation were performed before and after 24 weeks of treatment. After 24 weeks, both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were decreased significantly and by the same degree in each treatment group. However, valsartan but not amlodipine decreased plasma OPN levels (baseline and 24-week data-valsartan: 614±224 ng ml À1, 472±268 ng ml À1 , P ¼ 0.006; amlodipine: 680 ± 151 ng ml À1 , 687 ± 234 ng ml À1 , P40.999). A positive correlation between the reduction in OPN and the log natural (ln) C-reactive protein (CRP) was seen in the valsartan-treated group. Stepwise regression analysis showed that treatment with valsartan and the reduction of ln CRP were associated with the reduction in OPN levels, and this association was independent of the reduction in SBP or aldosterone levels (valsartan: b ¼ 0.332, P ¼ 0.026; ln CRP reduction: b ¼ 0.366, P ¼ 0.015). These results suggest that suppression of the RAAS and inflammation may decrease plasma OPN levels.

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Hypoxia Stimulates Osteopontin Expression and Proliferation of Cultured Vascular Smooth Muscle Cells

Cited by 91 publications

References 50 publications

Wogonin suppresses osteopontin expression in adipocytes by activating PPARα

Wogonin suppresses osteopontin expression in adipocytes by activating PPARα

Expression of Osteopontin Correlates with Portal Biliary Proliferation and Fibrosis in Biliary Atresia

Angiotensin II receptor blockade with valsartan decreases plasma osteopontin levels in patients with essential hypertension

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