Hydrogen Sulfide Prevents Elastin Loss and Attenuates Calcification Induced by High Glucose in Smooth Muscle Cells through Suppression of Stat3/Cathepsin S Signaling Pathway

Abstract

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 (H2S), 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 H2S 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 H2S may directly regulate Cys259 residue in Stat3 and then impair its signaling function. Our data indicate that H2S may attenuate vascular calcification by upregulating elastin level through the inhibition of Stat3/CAS signaling.

Role of SGK1 in the Osteogenic Transdifferentiation and Calcification of Vascular Smooth Muscle Cells Promoted by Hyperglycemic Conditions

“…In accordance with previous reports [ 16 , 17 , 39 ], the present observations show that high glucose directly promotes the osteogenic transdifferentiation of VSMCs, although relatively high glucose concentrations were required. In in vitro models of high glucose-induced VSMC calcification, the glucose levels required to induce a response in VSMCs presumably vary with the different origins of the cells and/or the cell culture medium used in experiments [ 16 , 17 , 39 , 40 ]. The effects of high glucose conditions were not mimicked by mannitol, which has been used as an osmotic control for high glucose-induced VSMC calcification processes [ 41 , 42 ].…”

“…Hyperglycemia was described to play a crucial role in the pathophysiology of vascular calcification [ 15 ]. High glucose was suggested to directly promote vascular calcification [ 15 , 16 , 17 ]. In addition, hyperglycemia may lead to the glycation of proteins and lipids and the increased formation of advanced glycation end products (AGEs) [ 18 ], additional key factors that drive vascular calcification [ 18 , 19 , 20 , 21 ].…”

“…Moreover, a key osteogenic enzyme in this process is tissue-nonspecific alkaline phosphatase (ALPL), which cleaves the endogenous calcification inhibitor pyrophosphate to allow unrestrained calcification [ 7 , 25 ]. Hyperglycemia and AGEs promote the osteogenic transdifferentiation of VSMCs to enhance vascular calcification [ 15 , 16 , 19 , 20 ], but the cellular mechanisms involved are still elusive.…”

Polysulfide and Hydrogen Sulfide Ameliorate Cisplatin-Induced Nephrotoxicity and Renal Inflammation through Persulfidating STAT3 and IKKβ

“…It has been found that H 2 S could inactivate IKKβ via persulfidating IKKβ at cysteine 179, thus inhibiting NF-κB activation and the subsequent inflammation response [ 23 ]. We recently reported that H 2 S directly induced the persulfidation of STAT3 at cysteine 259 and inactivated STAT3-mediated vascular calcification [ 25 ]. On the basis of these studies, we examined whether polysulfide and H 2 S inhibited the STAT3 and IKKβ signaling pathways via the persulfidation of them.…”

H2S donor improves heart function and vascular relaxation in diabetes

“…H 2 S has antioxidant and anti-inflammation activity. Recent studies demonstrated that H 2 S donors have therapeutic potential for ageing, 3 cardiovascular, [4][5][6][7] neurodegenerative 4 and gastrointestinal diseases. 5 According to studies, hydrogen sulphide has important protective effects in the complications associated with diabetes, such as endothelial dysfunction, retinopathy, cardiomyopathy and nephropathy.…”