title: HSP70 increases extracellular matrix production by human vascular smooth muscle through TGF-β1 up-regulation.
abstract: The circulating levels of heat shock proteins (HSP) are increased in cardiovascular diseases; however, the implication of this for the fibrotic process typical of such diseases remains unclear. HSP70 can interact with the vascular smooth muscle cells (SMC), the major producer of extracellular matrix (ECM) proteins, through the Toll-like receptors 4 (TLR4). The transforming growth factor type-β1 (TGF-β1) is a well known vascular pro-fibrotic cytokine that is regulated in part by AP-1-dependent transcriptional mechanisms. We hypothesized that extracellular HSP70 could interact with SMCs, inducing TGF-β1 synthesis and subsequent changes in the vascular ECM. We demonstrate that extracellular HSP70 binds to human aorta SMC TLR4, which up-regulates the AP-1-dependent transcriptional activity of the TGF-β1 promoter. This is achieved through the mitogen activated protein kinases JNK and ERK, as demonstrated by the use of specific blockers and the knockdown of TLR4 with specific small interfering RNAs. The TGF-β1 upregulation increase the expression of the ECM proteins type I collagen and fibronectin. This novel observation may elucidate the mechanisms by which HSP70 contributes in the inflammation and fibrosis present in atherosclerosis and other fibrosis-related diseases.
authors.affiliation: Department of Physiology, Universidad de Alcalá, Alcalá de Henares, Instituto Reina Sofía Investigación Nefrológica and RedInRen (Redes Temáticas de Investigación Cooperativa en Salud from Instituto de Salud Carlos III), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: González-Ramos
authors.forename: Laura
authors.initials: L
authors.lastname: Calleros
authors.forename: Susana
authors.initials: S
authors.lastname: López-Ongil
authors.forename: Viviana
authors.initials: V
authors.lastname: Raoch
authors.forename: Mercedes
authors.initials: M
authors.lastname: Griera
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodríguez-Puyol
authors.forename: Sergio
authors.initials: S
authors.lastname: de Frutos
authors.forename: Diego
authors.initials: D
authors.lastname: Rodríguez-Puyol
mesh_terms: D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D024042:Collagen Type I; D005353:Fibronectins; D018840:HSP70 Heat-Shock Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D020928:Mitogen-Activated Protein Kinases