Apelin-13 attenuates high glucose-induced calcification of MOVAS cells by regulating MAPKs and PI3K/AKT pathways and ROS-mediated signals

Zhang, Pu; Wang, Aiping; Yang, Hongpeng; Ai, Lei; Zhang, Hongjun; Wang, Yongmei; Bi, Yanling; Fan, Hao; Gao, Jing; Zhang, Huanyi; Liu, Jianzhu

doi:10.1016/j.biopha.2020.110271

Cited by 20 publications

(14 citation statements)

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“…Moreover, evidence shows that elevated Pi induces both MAPK and PI3K/Akt pathways in diverse human cells [ 176 ]. Further triggers of vascular calcification, such as oxLDL, high glucose, and H 2 O 2 , have been shown to induce osteochondrogenic transdifferentiation of VSMCs via the activation of both MAPK and PI3K/Akt signaling pathways [ 84 , 177 , 178 , 179 ].…”

Section: Redox Regulation Of Osteochondrogenic Signal Transductionmentioning

confidence: 99%

Regulation of Vascular Calcification by Reactive Oxygen Species

2020

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Vascular calcification is the deposition of hydroxyapatite crystals in the medial or intimal layers of arteries that is usually associated with other pathological conditions including but not limited to chronic kidney disease, atherosclerosis and diabetes. Calcification is an active, cell-regulated process involving the phenotype transition of vascular smooth muscle cells (VSMCs) from contractile to osteoblast/chondrocyte-like cells. Diverse triggers and signal transduction pathways have been identified behind vascular calcification. In this review, we focus on the role of reactive oxygen species (ROS) in the osteochondrogenic phenotype switch of VSMCs and subsequent calcification. Vascular calcification is associated with elevated ROS production. Excessive ROS contribute to the activation of certain osteochondrogenic signal transduction pathways, thereby accelerating osteochondrogenic transdifferentiation of VSMCs. Inhibition of ROS production and ROS scavengers and activation of endogenous protective mechanisms are promising therapeutic approaches in the prevention of osteochondrogenic transdifferentiation of VSMCs and subsequent vascular calcification. The present review discusses the formation and actions of excess ROS in different experimental models of calcification, and the potential of ROS-lowering strategies in the prevention of this deleterious condition.

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Section: Redox Regulation Of Osteochondrogenic Signal Transductionmentioning

confidence: 99%

Regulation of Vascular Calcification by Reactive Oxygen Species

2020

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“…We employed immortalized Ea.hy926 cell cultures with similar characteristics with primary human endothelial cells, such as HAECs, that are more stable and easier to maintain than primary human cultured ECs [ 54 ]. In recent years, different studies investigated vascular calcification utilizing immortalized line, such as mouse VSMC line MOVAS-1 cells with a SMCs-specific phenotype [ 55 , 56 , 57 ]. Moreover, other studies evaluated aortic valve disease and its related processes, as well as calcification, using immortalized cell lines derived from sheep and rats [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Uremic Toxin Lanthionine Induces Endothelial Cell Mineralization In Vitro

et al. 2022

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Vascular calcification (VC) is a pathological event caused by the unusual deposition of minerals in the vascular system, representing the leading cause of cardiovascular mortality in chronic kidney disease (CKD). In CKD, the deregulation of calcium and phosphate metabolism, along with the effect of several uremic toxins, act as key processes conveying altered mineralization. In this work, we tested the ability of lanthionine, a novel uremic toxin, to promote calcification in human endothelial cell cultures (Ea.hy926). We evaluated the effects of lanthionine, at a concentration similar to that actually detected in CKD patients, alone and under pro-calcifying culture conditions using calcium and phosphate. In pro-calcific culture conditions, lanthionine increased both the intracellular and extracellular calcium content and induced the expression of Bone Morphogenetic Protein 2 (BMP2) and RUNX Family Transcription Factor 2 (RUNX2). Lanthionine treatment, in pro-calcifying conditions, raised levels of tissue-nonspecific alkaline phosphatase (ALPL), whose expression also overlapped with Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1) gene expression, suggesting a possible role of the latter gene in the activation of ALPL. In addition, treatment with lanthionine alone or in combination with calcium and phosphate reduced Inorganic Pyrophosphate Transport Regulator (ANKH) gene expression, a protective factor toward the mineralizing process. Moreover, lanthionine in a pro-calcifying condition induced the activation of ERK1/2, which is not associated with an increase in DKK1 protein levels. Our data underscored a link between mineral disease and the alterations of sulfur amino acid metabolisms at a cell and molecular level. These results set the basis for the understanding of the link between uremic toxins and mineral-bone disorder during CKD progression.

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“…In ECs, apelin has been shown to induce the release of nitric oxide (NO) and to promote cell proliferation and vascular healing ( 25 – 27 ). Importantly, apelin has also been shown to inhibit the proliferation and migration of murine aortic SMCs ( 28 ). As the effect of empagliflozin on SMCs, the apelin-dependent regulation of SMC function has been reported to be mediated through ROS.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin prevents neointima formation by impairing smooth muscle cell proliferation and accelerating endothelial regeneration

Dutzmann

Bode

Kalies

et al. 2022

Front. Cardiovasc. Med.

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BackgroundEmpagliflozin, an inhibitor of the sodium glucose co-transporter 2 (SGLT2) and developed as an anti-diabetic agent exerts additional beneficial effects on heart failure outcomes. However, the effect of empagliflozin on vascular cell function and vascular remodeling processes remains largely elusive.Methods/ResultsImmunocytochemistry and immunoblotting revealed SGLT2 to be expressed in human smooth muscle (SMC) and endothelial cells (EC) as well as in murine femoral arteries. In vitro, empagliflozin reduced serum-induced proliferation and migration of human diabetic and non-diabetic SMCs in a dose-dependent manner. In contrast, empagliflozin significantly increased the cell count and migration capacity of human diabetic ECs, but not of human non-diabetic ECs. In vivo, application of empagliflozin resulted in a reduced number of proliferating neointimal cells in response to femoral artery wire-injury in C57BL/6J mice and prevented neointima formation. Comparable effects were observed in a streptozocin-induced diabetic model of apolipoprotein E–/– mice. Conclusive to the in vitro-results, re-endothelialization was not significantly affected in C57BL/6 mice, but improved in diabetic mice after treatment with empagliflozin assessed by Evan’s Blue staining 3 days after electric denudation of the carotid artery. Ribonucleic acid (RNA) sequencing (RNA-seq) of human SMCs identified the vasoactive peptide apelin to be decisively regulated in response to empagliflozin treatment. Recombinant apelin mimicked the in vitro-effects of empagliflozin in ECs and SMCs.ConclusionEmpagliflozin significantly reduces serum-induced proliferation and migration of SMCs in vitro and prevents neointima formation in vivo, while augmenting EC proliferation in vitro and re-endothelialization in vivo after vascular injury. These data document the functional impact of empagliflozin on vascular human SMCs and ECs and vascular remodeling in mice for the first time.

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Apelin-13 attenuates high glucose-induced calcification of MOVAS cells by regulating MAPKs and PI3K/AKT pathways and ROS-mediated signals

Cited by 20 publications

References 41 publications

Regulation of Vascular Calcification by Reactive Oxygen Species

Regulation of Vascular Calcification by Reactive Oxygen Species

Uremic Toxin Lanthionine Induces Endothelial Cell Mineralization In Vitro

Empagliflozin prevents neointima formation by impairing smooth muscle cell proliferation and accelerating endothelial regeneration

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