Laminar shear stress-provoked cytoskeletal changes are mediated by epigenetic reprogramming of TIMP1 in human primary smooth muscle cells

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dc.contributor.authorda Silva, Rodrigo A. [UNESP]
dc.contributor.authorFernandes, Célio Jr da C. [UNESP]
dc.contributor.authorFeltran, Geórgia da S. [UNESP]
dc.contributor.authorGomes, Anderson M. [UNESP]
dc.contributor.authorde Camargo Andrade, Amanda Fantini [UNESP]
dc.contributor.authorAndia, Denise C.
dc.contributor.authorPeppelenbosch, Maikel P.
dc.contributor.authorZambuzzi, Willian F. [UNESP]
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionUNIP
dc.contributor.institutionUniversity Medical Center Rotterdam
dc.date.accessioned2019-10-06T15:57:09Z
dc.date.available2019-10-06T15:57:09Z
dc.date.issued2019-05-01
dc.description.abstractWhereas endothelial responses to shear stress are well-characterized, the cell physiological effects of shear stress in smooth muscle cells (SMCs) remain largely obscure. As SMCs are directly challenged by shear stress after endothelial denuding injury following procedures such as angioplasty or endarterectomy, characterization of these responses represents an important scientific question. Hence we decided to contrast cytoskeletal reorganization, epigenetic reprogramming, signaling transduction, and changes in miRNA (miRs) profiles in primary human aortic smooth muscle cells (AoSMCs) between unstressed cells and cells exposed to shear stress. We observed that shear stress-provoked reorganization of the actin cytoskeleton in an apparently Cofilin-dependent fashion and which related to altered integrin signaling, apparently caused by remodeling of the extracellular matrix. The latter appeared a downstream effect of increased expression of matrix metalloproteinases and downregulation of tissue metalloproteinase inhibitor 1 (TIMP1) protein levels. In turn, these effects related to shear stress-provoked changes in expression and nuclear localization of the epigenetic regulators demethylases TET1, TET2, DNMT1, DNMT3A and DNMT3B, HDAC6, and SIRT1. Accordingly, TIMP1 promotor CpG hypomethylation was a prominent effect, and resulted in a significant increase in TIMP1 transcription, which may also have related increased expression of miRs involved in modulating TIMP1 translation. Thus epigenetic-reprogramming of TIMP1 emerges as critical element in smooth muscle responses to mechanical signals and as epigenetic machinery is amendable to pharmacological manipulation, this pathway may have important clinical consequences.en
dc.description.affiliationDepartment of Chemistry and Biochemistry Laboratory of Bioassays and Cellular Dynamics São Paulo State University (UNESP) Institute of Biosciences Campus Botucatu
dc.description.affiliationFaculdade de Odontologia Área de Pesquisa em Epigenética Universidade Paulista UNIP
dc.description.affiliationDepartment of Gastroenterology & Hepatology Erasmus MC University Medical Center Rotterdam
dc.description.affiliationElectron Microscopy Center São Paulo State University (UNESP) Institute of Biosciences campus Botucatu
dc.description.affiliationUnespDepartment of Chemistry and Biochemistry Laboratory of Bioassays and Cellular Dynamics São Paulo State University (UNESP) Institute of Biosciences Campus Botucatu
dc.description.affiliationUnespElectron Microscopy Center São Paulo State University (UNESP) Institute of Biosciences campus Botucatu
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipIdFAPESP: 2014/22689-3
dc.description.sponsorshipIdFAPESP: 2016/01139-0
dc.description.sponsorshipIdFAPESP: 2016/08888-9
dc.format.extent6382-6396
dc.identifierhttp://dx.doi.org/10.1002/jcp.27374
dc.identifier.citationJournal of Cellular Physiology, v. 234, n. 5, p. 6382-6396, 2019.
dc.identifier.doi10.1002/jcp.27374
dc.identifier.issn1097-4652
dc.identifier.issn0021-9541
dc.identifier.scopus2-s2.0-85053681932
dc.identifier.urihttp://hdl.handle.net/11449/188095
dc.language.isoeng
dc.relation.ispartofJournal of Cellular Physiology
dc.rights.accessRightsAcesso restrito
dc.sourceScopus
dc.subjectaortic smooth muscle cells
dc.subjectcytoskeleton
dc.subjectECM
dc.subjectendothelium
dc.subjectepigenetic
dc.subjectTIMP
dc.titleLaminar shear stress-provoked cytoskeletal changes are mediated by epigenetic reprogramming of TIMP1 in human primary smooth muscle cellsen
dc.typeArtigo
unesp.author.orcid0000-0001-9112-6028[7]
unesp.author.orcid0000-0002-4149-5965[8]

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Artigos - Química e Bioquímica - IBB
Botucatu - CME - Centro de Microscopia Eletrônica