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Cholesterol induces dedifferentiation of vascular smooth muscle cells by regulating monocyte chemotactic protein-1-induced protein 1.

ABSTRACT: OBJECTIVE:To discover the effect of cholesterol on dedifferentiation of VSMCs in vitro and the underlying mechanisms. METHODS:Vascular smooth muscle cells (VSMC) were employed to evaluate the role of cholesterol in regulating the dedifferentiation of VSMCs in vitro. Immunofluorescent staining, western blot, and RT-PCR were applied to uncover the inducing effect of cholesterol at a molecular level. RESULTS:We demonstrated that the cholesterol was capable of inducing the dedifferentiation of VSMCs. Mechanistic studies revealed that monocyte chemotactic protein-1-induced protein 1 (MCPIP1) composed the most influential factor in the regulation of VSMCs during the process of cholesterol induction. When MCPIP1 was overexpressed in VSMCs, the dedifferentiation, proliferation and migration of the cells was enhanced, and the expression of miR-145 was suppressed. In contrast, knocking down MCPIP1 by siRNA promoted the differentiation and prohibited the migration of VSMCs after cholesterol treatment. These results demonstrate that MCPIP1 plays an important role in regulating cholesterol-induced dedifferentiation of VSMCs in vitro.

SUBMITTER: Shu B

PROVIDER: S-EPMC6949835 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Cholesterol induces dedifferentiation of vascular smooth muscle cells by regulating monocyte chemotactic protein-1-induced protein 1.

Shu Bo B Zhuo Ming M Liu Zhijiang Z Lu Zhe Z Qian Minzhang M

International journal of clinical and experimental pathology 20190901 9

<h4>Objective</h4>To discover the effect of cholesterol on dedifferentiation of VSMCs <i>in vitro</i> and the underlying mechanisms.<h4>Methods</h4>Vascular smooth muscle cells (VSMC) were employed to evaluate the role of cholesterol in regulating the dedifferentiation of VSMCs <i>in vitro</i>. Immunofluorescent staining, western blot, and RT-PCR were applied to uncover the inducing effect of cholesterol at a molecular level.<h4>Results</h4>We demonstrated that the cholesterol was capable of ind ...[more]

PMID: 31934169

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Project description:Restenosis, re-narrowing of arterial lumen following intervention for cardiovascular disease, remains a major issue limiting the long-term therapeutic efficacy of treatment. The signaling molecules, TGFβ (transforming growth factor-beta) and Smad3, play important roles in vascular restenosis, but very little is yet known about the down-stream dynamics in global protein expression and phosphorylation. Here, we develop a highly multiplexed quantitative proteomic and phosphoproteomic strategy employing 12-plex N,N-dimethyl leucine (DiLeu) isobaric tags and The DiLeu Tool software to globally assess protein expression and phosphorylation changes in smooth muscle cells (SMCs) treated with TGFβ/Smad3 and/or SDF-1α (stromal cell-derived factor). A total of 4086 proteins were quantified in the combined dataset of proteome and phosphoproteome across 12-plex DiLeu-labeled SMC samples. 2317 localized phosphorylation sites were quantified, corresponding to 1193 phosphoproteins. TGFβ/Smad3 induced up-regulation of 40 phosphosites and down-regulation of 50 phosphosites, and TGFβ/Smad3-specific SDF-1α exclusively facilitated up-regulation of 27 phosphosites and down-regulation of 47 phosphosites. TGFβ/Smad3 inhibited the expression of contractile-associated proteins including smooth muscle myosin heavy chain, calponin, cardiac muscle alpha-actin, and smooth muscle protein 22α. Gene ontology and pathway enrichment analysis revealed that elevated TGFβ/Smad3 activated cell proliferation and TGFβ signaling pathway, sequentially stimulating phosphorylation of CXCR4 (C-X-C chemokine receptor 4). SDF-1α/CXCR4 activated extracellular signal-regulating kinase signaling pathway and facilitated the expression of synthetic marker, osteopontin, which was validated through targeted analysis. These findings provide new insights into the mechanisms of TGFβ regulated SMC dedifferentiation, as well as new avenues for designing effective therapeutics for vascular disease.

Dataset Information

Cholesterol induces dedifferentiation of vascular smooth muscle cells by regulating monocyte chemotactic protein-1-induced protein 1.

Publications

Cholesterol induces dedifferentiation of vascular smooth muscle cells by regulating monocyte chemotactic protein-1-induced protein 1.

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