Cyclooxygenase-2/sclerostin mediates TGF-β1-induced calcification in vascular smooth muscle cells and rats undergoing renal failure

He, Fang; Li, Ling; Li, Peipei; Deng, Yan; Yang, Yuanyuan; Deng, Yi-Xuan; Luo, Honghong; Yao, Xintong; Su, Yuxi; Gan, Hua

doi:10.18632/aging.103827

Cited by 12 publications

(18 citation statements)

References 42 publications

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“…It has been suggested that the increase in sclerostin protein in chronic renal disease patients might be related to the increase in osteocyte production [ 52 , 53 ]. Studies have confirmed that sclerostin is upregulated in the process of calcification of vascular smooth muscle cells in vitro [ 14 ]. The Wnt signaling pathway regulates the process of cell proliferation, cell differentiation, and tissue patterning.…”

Section: Discussionmentioning

confidence: 97%

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Circulating miRNA-29b and Sclerostin Levels Correlate with Coronary Artery Calcification and Cardiovascular Events in Maintenance Hemodialysis Patients

Pan

et al. 2021

Cardiology Research and Practice

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Objective. Coronary artery calcification (CAC) is a common complication in end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis (MHD), and the extent of CAC is a predominant predictor of cardiovascular outcomes in MHD patients. In this study, we sought to uncover the relationship between circulating miRNA-29b, sclerostin levels, CAC, and cardiovascular events (CVEs) in MHD patients. Methods. This study recruited patients receiving MHD for at least three months in the Hainan General Hospital between January 2016 and June 2019, and all patients were followed up 24 months for CVEs. The serum level of sclerostin was determined by enzyme-linked immunosorbent assay (ELISA) and miRNA-29b expression by real-time qPCR (RT-qPCR). All patients received cardiac CT scans to evaluate CAC, and CAC scores were expressed in Agatston units. The MHD patients with CACs <100 were arranged into the CAC (<100) group, those with 100–400 CACs into the CAC (100–400) group, and those with CACs >400 into the CAC (>400) group. Net reclassification index (NRI) and integrated discrimination index (IDI) were calculated to assess the predictive performance of serum sclerostin level for the occurrence of CVEs. Results. Compared with the CAC (<100) group, the CAC (>400) group had higher proportions of older patients, hypertension and diabetes mellitus patients, longer dialysis duration, higher mean arterial pressure (MAP), higher levels of high-sensitivity C-reactive protein (hs-CRP), alkaline phosphatase (ALP), and phosphate ( P < 0.05 ). It was found that the CAC (100–400) and CAC (>400) groups exhibited higher serum levels of sclerostin but lower levels of miRNA-29b than the CAC (<100) group ( P < 0.05 ) and the CAC (>400) group had a higher level of sclerostin and a lower level of miRNA-29b than the CAC (100–400) group ( P < 0.05 ). The circulating level of miRNA-29b was negatively correlated with the serum level of sclerostin in MHD patients (r = −0.329, P < 0.01 ). The multivariate logistic regression analysis showed that hs-CRP, phosphate, sclerostin, and miRNA-29b were independent risk factors for CAC in MHD patients ( P < 0.05 , Table 2). ROC for prediction of CAC by sclerostin yielded 0.773 AUC with 95% CI 0.683–0.864 ( P < 0.01 ). As depicted by Kaplan–Meier curves of CVE incidence in MHD patients according to median sclerostin (491.88 pg/mL) and median miRNA-29b (Ct = 25.15), we found that serum levels of sclerostin and miRNA-29b were correlated with the incidence of CVEs in MHD patients. When a new model was used to predict the incidence of CVEs, NRI 95% CI was 0.60 (0.16–1.03) ( P < 0.05 ) and IDI 95% CI was 0.002 (−0.014 to 0.025) ( P < 0.05 ), suggesting that sclerostin added into the old model could improve the prediction of the incidence of CVEs. Conclusions. These data suggest that circulating miRNA-29b and sclerostin levels are correlated with CAC and incidence of CVEs in MHD patients. Higher sclerostin and lower miRNA-29b may serve as independent risk factors for the incidence of CVEs in MHD patients.

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Section: Discussionmentioning

confidence: 97%

“…It has been confirmed that sclerostin expression was associated with induced calcification in vascular smooth muscle cells [ 13 , 14 ]. Sclerostin, as an osteocyte-specific protein, has become a marker of clinical and subclinical vascular diseases.…”

Section: Introductionmentioning

confidence: 95%

Circulating miRNA-29b and Sclerostin Levels Correlate with Coronary Artery Calcification and Cardiovascular Events in Maintenance Hemodialysis Patients

Pan

et al. 2021

Cardiology Research and Practice

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“…6 A). Stat3 activation can also increase TGF-β1 signaling that promotes the calcification of VSMCs [ 31 , 32 ]. In this experiment, NaHS treatment indeed reduced the TGF-β1 protein expression in aorta of DN rats.…”

Section: Resultsmentioning

confidence: 99%

“…Especially important, Stat3-mediated activation of CAS involved in calcification of VSMCs has been confirmed under the stimulation of high levels of glucose and phosphorus [ 13 ]. STAT3 also enhances hepatic fibrosis through the upregulation of TGF-β1 expression [ 31 ], which contributes to the calcification of VSMCs involving the mechanisms of TGF-β1 pathway [ 32 ]. It has been previously shown that elastin degradation products work synergistically with TGF-β1 to induce osteogenesis in vascular smooth muscle cells [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Hydrogen sulfide prevents arterial medial calcification in rats with diabetic nephropathy

Wang

Zhou

Wang

et al. 2021

BMC Cardiovasc Disord

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Background Arterial medial calcification (AMC) is associated with a high incidence of cardiovascular risk in patients with type 2 diabetes and chronic kidney disease. Here, we tested whether hydrogen sulfide (H2S) can prevent AMC in rats with diabetic nephropathy (DN). Methods DN was induced by a single injection of streptozotocin and high-fat diet (45% kcal as fat) containing 0.75% adenine in Sprague–Dawley rats for 8 weeks. Results Rats with DN displayed obvious calcification in aorta, and this was significantly alleviated by Sodium Hydrosulfide (NaHS, a H2S donor, 50 μmol/kg/day for 8 weeks) treatment through decreasing calcium and phosphorus content, ALP activity and calcium deposition in aorta. Interestingly, the main endogenous H2S generating enzyme activity and protein expression of cystathionine-γ-lyase (CSE) were largely reduced in the arterial wall of DN rats. Exogenous NaHS treatment restored CSE activity and its expression, inhibited aortic osteogenic transformation by upregulating phenotypic markers of smooth muscle cells SMα-actin and SM22α, and downregulating core binding factor α-1 (Cbfα-1, a key factor for bone formation), protein expressions in rats with DN when compared to the control group. NaHS administration also significantly reduced Stat3 activation, cathepsin S (CAS) activity and TGF-β1 protein level, and improved aortic elastin expression. Conclusions H2S may have a clinical significance for treating AMC in people with DN by reducing Stat3 activation, CAS activity, TGF-β1 level and increasing local elastin level.

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“…Furthermore, CREB mediates the pro-calcific effects of low potassium conditions in VSMCs [ 61 ]. CREB may also be involved in the pro-calcific effects of transforming growth factor β1 [ 27 ]. The present observations show a transient activation of PKA/CREB after isoproterenol exposure.…”

Section: Discussionmentioning

confidence: 99%

Increased β-adrenergic stimulation augments vascular smooth muscle cell calcification via PKA/CREB signalling

Moser

Poetsch

Estepa

et al. 2021

Pflugers Arch - Eur J Physiol

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In chronic kidney disease (CKD), hyperphosphatemia promotes medial vascular calcification, a process augmented by osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). VSMC function is regulated by sympathetic innervation, and these cells express α- and β-adrenergic receptors. The present study explored the effects of β2-adrenergic stimulation by isoproterenol on VSMC calcification. Experiments were performed in primary human aortic VSMCs treated with isoproterenol during control or high phosphate conditions. As a result, isoproterenol dose dependently up-regulated the expression of osteogenic markers core-binding factor α-1 (CBFA1) and tissue-nonspecific alkaline phosphatase (ALPL) in VSMCs. Furthermore, prolonged isoproterenol exposure augmented phosphate-induced calcification of VSMCs. Isoproterenol increased the activation of PKA and CREB, while knockdown of the PKA catalytic subunit α (PRKACA) or of CREB1 genes was able to suppress the pro-calcific effects of isoproterenol in VSMCs. β2-adrenergic receptor silencing or inhibition with the selective antagonist ICI 118,551 blocked isoproterenol-induced osteogenic signalling in VSMCs. The present observations imply a pro-calcific effect of β2-adrenergic overstimulation in VSMCs, which is mediated, at least partly, by PKA/CREB signalling. These observations may support a link between sympathetic overactivity in CKD and vascular calcification.

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Cyclooxygenase-2/sclerostin mediates TGF-β1-induced calcification in vascular smooth muscle cells and rats undergoing renal failure

Cited by 12 publications

References 42 publications

Circulating miRNA-29b and Sclerostin Levels Correlate with Coronary Artery Calcification and Cardiovascular Events in Maintenance Hemodialysis Patients

Circulating miRNA-29b and Sclerostin Levels Correlate with Coronary Artery Calcification and Cardiovascular Events in Maintenance Hemodialysis Patients

Hydrogen sulfide prevents arterial medial calcification in rats with diabetic nephropathy

Increased β-adrenergic stimulation augments vascular smooth muscle cell calcification via PKA/CREB signalling

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