title: Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells That Contribute to the Fibrous Cap.
abstract: Recent genome wide association studies have identified a number of genes that contribute to the risk for coronary heart disease. One such gene, TCF21, encodes a basic-helix-loop-helix transcription factor believed to serve a critical role in the development of epicardial progenitor cells that give rise to coronary artery smooth muscle cells (SMC) and cardiac fibroblasts. Using reporter gene and immunolocalization studies with mouse and human tissues we have found that vascular TCF21 expression in the adult is restricted primarily to adventitial cells associated with coronary arteries and also medial SMC in the proximal aorta of mouse. Genome wide RNA-Seq studies in human coronary artery SMC (HCASMC) with siRNA knockdown found a number of putative TCF21 downstream pathways identified by enrichment of terms related to CAD, including "vascular disease," "disorder of artery," and "occlusion of artery," as well as disease-related cellular functions including "cellular movement" and "cellular growth and proliferation." In vitro studies in HCASMC demonstrated that TCF21 expression promotes proliferation and migration and inhibits SMC lineage marker expression. Detailed in situ expression studies with reporter gene and lineage tracing revealed that vascular wall cells expressing Tcf21 before disease initiation migrate into vascular lesions of ApoE-/- and Ldlr-/- mice. While Tcf21 lineage traced cells are distributed throughout the early lesions, in mature lesions they contribute to the formation of a subcapsular layer of cells, and others become associated with the fibrous cap. The lineage traced fibrous cap cells activate expression of SMC markers and growth factor receptor genes. Taken together, these data suggest that TCF21 may have a role regulating the differentiation state of SMC precursor cells that migrate into vascular lesions and contribute to the fibrous cap and more broadly, in view of the association of this gene with human CAD, provide evidence that these processes may be a mechanism for CAD risk attributable to the vascular wall.
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Sylvia T
authors.initials: ST
authors.lastname: Nurnberg
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Azad
authors.initials: A
authors.lastname: Raiesdana
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Ramendra
authors.initials: R
authors.lastname: Kundu
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Clint L
authors.initials: CL
authors.lastname: Miller
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Juyong B
authors.initials: JB
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Komal
authors.initials: K
authors.lastname: Arora
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Ivan
authors.initials: I
authors.lastname: Carcamo-Oribe
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Tellakula
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Vivek
authors.initials: V
authors.lastname: Nanda
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Nikitha
authors.initials: N
authors.lastname: Murthy
authors.affiliation: Department of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: William A
authors.initials: WA
authors.lastname: Boisvert
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: Ljubica
authors.initials: L
authors.lastname: Perisic
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: Silvia
authors.initials: S
authors.lastname: Aldi
authors.affiliation: Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Maegdefessel
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Milos
authors.initials: M
authors.lastname: Pjanic
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
authors.affiliation: Department of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Tallquist
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D013234:Stem Cells
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C112923:Tcf21 protein, mouse