Hydrogen Sulfide Prevents Elastin Loss and Attenuates Calcification Induced by High Glucose in Smooth Muscle Cells through Suppression of Stat3/Cathepsin S Signaling Pathway
Vascular calcification can be enhanced by hyperglycemia. Elastin loss in tunica media promotes the osteogenic transformation of smooth muscle cells (SMCs) and involves arterial medial calcification (AMC) that is associated with a high incidence of cardiovascular risk in patients with type 2 diabetes...
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doaj-1add03f0ad464c8f886ca617b223cc852020-11-24T21:31:59ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-08-012017420210.3390/ijms20174202ijms20174202Hydrogen Sulfide Prevents Elastin Loss and Attenuates Calcification Induced by High Glucose in Smooth Muscle Cells through Suppression of Stat3/Cathepsin S Signaling PathwayYe-Bo Zhou0Hong Zhou1Li Li2Ying Kang3Xu Cao4Zhi-Yuan Wu5Lei Ding6Gautam Sethi7Jin-Song Bian8Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, SingaporeDepartment of Physiology, Nanjing Medical University, Nanjing 211166, ChinaDepartment of Pathophysiology, Xuzhou Medical University, Xuzhou 221004, ChinaDepartment of Physiology, Nanjing Medical University, Nanjing 211166, ChinaDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, SingaporeDepartment of Pathophysiology, Xuzhou Medical University, Xuzhou 221004, ChinaDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, SingaporeVascular calcification can be enhanced by hyperglycemia. Elastin loss in tunica media promotes the osteogenic transformation of smooth muscle cells (SMCs) and involves arterial medial calcification (AMC) that is associated with a high incidence of cardiovascular risk in patients with type 2 diabetes. Here, we tested whether hydrogen sulfide (H<sub>2</sub>S), an endogenous gaseous mediator, can prevent elastin loss and attenuate calcification induced by high glucose in SMCs. Calcification was induced by high glucose (4500 mg/L) in human aortic SMCs (HASMCs) under the condition of calcifying medium containing 10 mM β-glycerophosphate (β-GP). The experiments showed that NaHS (an H<sub>2</sub>S donor, 100 μM) mitigated the calcification of HASMCs treated with high glucose by decreasing calcium and phosphorus levels, calcium deposition and ALP activity and inhibited osteogenic transformation by increasing SMα-actin and SM22α, two phenotypic markers of smooth muscle cells, and decreasing core binding factor α-1 (Cbfα-1), a key factor in bone formation, protein expressions in HASMCs. Moreover, NaHS administration inhibited the activation of Stat3, cathepsin S (CAS) activity and its expression, but increased the level of elastin protein. Pharmacological inhibition or gene silencing Stat3 not only reversed elastin loss, but also attenuated CAS expression. Inhibition of CAS alleviated, while CAS overexpression exacerbated, elastin loss. Interestingly, overexpression of wild type (WT)-Stat3, but not its mutant C259S, elevated CAS protein expression and reduced elastin level. Moreover, NaHS induced S-sulfhydration in WT, but not in the C259S Stat3. These data suggest that H<sub>2</sub>S may directly regulate Cys259 residue in Stat3 and then impair its signaling function. Our data indicate that H<sub>2</sub>S may attenuate vascular calcification by upregulating elastin level through the inhibition of Stat3/CAS signaling.https://www.mdpi.com/1422-0067/20/17/4202hydrogen sulfidecalcificationsmooth muscle cellsStat3cathepsin Selastin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ye-Bo Zhou Hong Zhou Li Li Ying Kang Xu Cao Zhi-Yuan Wu Lei Ding Gautam Sethi Jin-Song Bian |
spellingShingle |
Ye-Bo Zhou Hong Zhou Li Li Ying Kang Xu Cao Zhi-Yuan Wu Lei Ding Gautam Sethi Jin-Song Bian Hydrogen Sulfide Prevents Elastin Loss and Attenuates Calcification Induced by High Glucose in Smooth Muscle Cells through Suppression of Stat3/Cathepsin S Signaling Pathway International Journal of Molecular Sciences hydrogen sulfide calcification smooth muscle cells Stat3 cathepsin S elastin |
author_facet |
Ye-Bo Zhou Hong Zhou Li Li Ying Kang Xu Cao Zhi-Yuan Wu Lei Ding Gautam Sethi Jin-Song Bian |
author_sort |
Ye-Bo Zhou |
title |
Hydrogen Sulfide Prevents Elastin Loss and Attenuates Calcification Induced by High Glucose in Smooth Muscle Cells through Suppression of Stat3/Cathepsin S Signaling Pathway |
title_short |
Hydrogen Sulfide Prevents Elastin Loss and Attenuates Calcification Induced by High Glucose in Smooth Muscle Cells through Suppression of Stat3/Cathepsin S Signaling Pathway |
title_full |
Hydrogen Sulfide Prevents Elastin Loss and Attenuates Calcification Induced by High Glucose in Smooth Muscle Cells through Suppression of Stat3/Cathepsin S Signaling Pathway |
title_fullStr |
Hydrogen Sulfide Prevents Elastin Loss and Attenuates Calcification Induced by High Glucose in Smooth Muscle Cells through Suppression of Stat3/Cathepsin S Signaling Pathway |
title_full_unstemmed |
Hydrogen Sulfide Prevents Elastin Loss and Attenuates Calcification Induced by High Glucose in Smooth Muscle Cells through Suppression of Stat3/Cathepsin S Signaling Pathway |
title_sort |
hydrogen sulfide prevents elastin loss and attenuates calcification induced by high glucose in smooth muscle cells through suppression of stat3/cathepsin s signaling pathway |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-08-01 |
description |
Vascular calcification can be enhanced by hyperglycemia. Elastin loss in tunica media promotes the osteogenic transformation of smooth muscle cells (SMCs) and involves arterial medial calcification (AMC) that is associated with a high incidence of cardiovascular risk in patients with type 2 diabetes. Here, we tested whether hydrogen sulfide (H<sub>2</sub>S), an endogenous gaseous mediator, can prevent elastin loss and attenuate calcification induced by high glucose in SMCs. Calcification was induced by high glucose (4500 mg/L) in human aortic SMCs (HASMCs) under the condition of calcifying medium containing 10 mM β-glycerophosphate (β-GP). The experiments showed that NaHS (an H<sub>2</sub>S donor, 100 μM) mitigated the calcification of HASMCs treated with high glucose by decreasing calcium and phosphorus levels, calcium deposition and ALP activity and inhibited osteogenic transformation by increasing SMα-actin and SM22α, two phenotypic markers of smooth muscle cells, and decreasing core binding factor α-1 (Cbfα-1), a key factor in bone formation, protein expressions in HASMCs. Moreover, NaHS administration inhibited the activation of Stat3, cathepsin S (CAS) activity and its expression, but increased the level of elastin protein. Pharmacological inhibition or gene silencing Stat3 not only reversed elastin loss, but also attenuated CAS expression. Inhibition of CAS alleviated, while CAS overexpression exacerbated, elastin loss. Interestingly, overexpression of wild type (WT)-Stat3, but not its mutant C259S, elevated CAS protein expression and reduced elastin level. Moreover, NaHS induced S-sulfhydration in WT, but not in the C259S Stat3. These data suggest that H<sub>2</sub>S may directly regulate Cys259 residue in Stat3 and then impair its signaling function. Our data indicate that H<sub>2</sub>S may attenuate vascular calcification by upregulating elastin level through the inhibition of Stat3/CAS signaling. |
topic |
hydrogen sulfide calcification smooth muscle cells Stat3 cathepsin S elastin |
url |
https://www.mdpi.com/1422-0067/20/17/4202 |
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