Dataset Information

Attenuation of chondrogenic transformation in vascular smooth muscle by dietary quercetin in the MGP-deficient mouse model.

ABSTRACT:

Rationale

Cartilaginous metaplasia of vascular smooth muscle (VSM) is characteristic for arterial calcification in diabetes and uremia and in the background of genetic alterations in matrix Gla protein (MGP). A better understanding of the molecular details of this process is critical for the development of novel therapeutic approaches to VSM transformation and arterial calcification.

Objective

This study aimed to identify the effects of bioflavonoid quercetin on chondrogenic transformation and calcification of VSM in the MGP-null mouse model and upon TGF-?3 stimulation in vitro, and to characterize the associated alterations in cell signaling.

Methods and results

Molecular analysis revealed activation of ?-catenin signaling in cartilaginous metaplasia in Mgp-/- aortae in vivo and during chondrogenic transformation of VSMCs in vitro. Quercetin intercepted chondrogenic transformation of VSM and blocked activation of ?-catenin both in vivo and in vitro. Although dietary quercetin drastically attenuated calcifying cartilaginous metaplasia in Mgp-/- animals, approximately one-half of total vascular calcium mineral remained as depositions along elastic lamellae.

Conclusion

Quercetin is potent in preventing VSM chondrogenic transformation caused by diverse stimuli. Combined with the demonstrated efficiency of dietary quercetin in preventing ectopic chondrogenesis in the MGP-null vasculature, these findings indicate a potentially broad therapeutic applicability of this safe for human consumption bioflavonoid in the therapy of cardiovascular conditions linked to cartilaginous metaplasia of VSM. Elastocalcinosis is a major component of MGP-null vascular disease and is controlled by a mechanism different from chondrogenic transformation of VSM and not sensitive to quercetin.

SUBMITTER: Beazley KE

PROVIDER: S-EPMC3786963 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Attenuation of chondrogenic transformation in vascular smooth muscle by dietary quercetin in the MGP-deficient mouse model.

Beazley Kelly E KE Lima Florence F Borras Teresa T Nurminskaya Maria M

PloS one 20130930 9

<h4>Rationale</h4>Cartilaginous metaplasia of vascular smooth muscle (VSM) is characteristic for arterial calcification in diabetes and uremia and in the background of genetic alterations in matrix Gla protein (MGP). A better understanding of the molecular details of this process is critical for the development of novel therapeutic approaches to VSM transformation and arterial calcification.<h4>Objective</h4>This study aimed to identify the effects of bioflavonoid quercetin on chondrogenic trans ...[more]

PMID: 24098781

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Project description:Atherosclerosis (AT) is a chronic inflammatory disease characterized by the accumulation of inflammatory cells, lipoproteins and fibrous tissue in the walls of arteries. AT is the primary cause of heart attacks and stroke and is the leading cause of death in Western countries. To date, the pathogenesis of AT is not well-defined. Studies have shown that the dedifferentiation of contractile and quiescent vascular smooth muscle cells (SMC) to the proliferative, migratory and synthetic phenotype in the intima is pivotal for the onset and progression of AT. To further delineate the mechanisms underlying the pathogenesis of AT, we analyzed the early molecular pathways and networks involved in the SMC phenotype transformation.Quiescent human coronary artery SMCs were treated with minimally-oxidized LDL (moxLDL), for 3 hours and 21 hours, respectively. Transcriptomic data was generated for both time-points using microarrays and was subjected to pathway analysis using Gene Set Enrichment Analysis, GeneMANIA and Ingenuity software tools. Gene expression heat maps and pathways enriched in differentially expressed genes were compared to identify functional biological themes to elucidate early and late molecular mechanisms of moxLDL-induced SMC dedifferentiation.Differentially expressed genes were found to be enriched in cholesterol biosynthesis, inflammatory cytokines, chemokines, growth factors, cell cycle control and myogenic contraction themes. These pathways are consistent with inflammatory responses, cell proliferation, migration and ECM production, which are characteristic of SMC dedifferentiation. Furthermore, up-regulation of cholesterol synthesis and dysregulation of cholesterol metabolism was observed in moxLDL-induced SMC. These observations are consistent with the accumulation of cholesterol and oxidized cholesterol esters, which induce proinflammatory reactions during atherogenesis. Our data implicate for the first time IL12, IFN-?, HGF, CSF3, and VEGF signaling in SMC phenotype transformation. GPCR signaling, HBP1 (repressor of cyclin D1 and CDKN1B), and ID2 and ZEB1 transcriptional regulators were also found to have important roles in SMC dedifferentiation. Several microRNAs were observed to regulate the SMC phenotype transformation via an interaction with IFN-? pathway. Also, several "nexus" genes in complex networks, including components of the multi-subunit enzyme complex involved in the terminal stages of cholesterol synthesis, microRNAs (miR-203, miR-511, miR-590-3p, miR-346*/miR- 1207-5p/miR-4763-3p), GPCR proteins (GPR1, GPR64, GPRC5A, GPR171, GPR176, GPR32, GPR25, GPR124) and signal transduction pathways, were found to be regulated.The systems biology analysis of the in vitro model of moxLDL-induced VSMC phenotype transformation was associated with the regulation of several genes not previously implicated in SMC phenotype transformation. The identification of these potential candidate genes enable hypothesis generation and in vivo functional experimentation (such as gain and loss-of-function studies) to establish causality with the process of SMC phenotype transformation and atherogenesis.

Dataset Information

Attenuation of chondrogenic transformation in vascular smooth muscle by dietary quercetin in the MGP-deficient mouse model.

Rationale

Objective

Methods and results

Conclusion

Publications

Attenuation of chondrogenic transformation in vascular smooth muscle by dietary quercetin in the MGP-deficient mouse model.

Similar Datasets

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