title: HMGB1-Driven Inflammation and Intimal Hyperplasia After Arterial Injury Involves Cell-Specific Actions Mediated by TLR4.
abstract: OBJECTIVE
  Endoluminal vascular interventions such as angioplasty initiate a sterile inflammatory response resulting from local tissue damage. This response drives the development of intimal hyperplasia (IH) that, in turn, can lead to arterial occlusion. We hypothesized that the ubiquitous nuclear protein and damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1), is one of the endogenous mediators that activates processes leading to IH after endoluminal injury to the arterial wall. The aim of this study is to investigate whether approaches that reduce the levels of HMGB1 or inhibit its activity suppresses IH after arterial injury.
  
  
  RESULTS
  Here, we show that HMGB1 regulates IH in a mouse carotid wire injury model. Induced genetic deletion or neutralization of HMGB1 prevents IH, monocyte recruitment, and smooth muscle cell growth factor production after endoluminal carotid artery injury. A specific inhibitor of HMGB1 myeloid differentiation factor 2-toll-like receptor 4 (TLR4) interaction, P5779, also significantly inhibits IH. HMGB1 deletion is mimicked in this model by global deletion of TLR4 and partially replicated by myeloid-specific deletion of TLR4 but not TLR2 or receptor for advanced glycation endproducts deletion. The specific HMGB1 isoform known to activate TLR4 signaling (disulfide HMGB1) stimulates smooth muscle cell to migrate and produce monocyte chemotactic protein 1/CCL2) via TLR4. Macrophages produce smooth muscle cell mitogens in response to disulfide HMGB1 also in a TLR4/myeloid differentiation primary response gene (88)/Trif-dependent manner.
  
  
  CONCLUSIONS
  These findings place HMGB1 and its receptor, TLR4 as critical regulators of the events that drive the inflammation leading to IH after endoluminal arterial injury and identify this pathway as a possible therapeutic target to limit IH to attenuate damage-associated molecular pattern molecule-mediated vascular inflammatory responses.
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Jingjing
authors.initials: J
authors.lastname: Cai
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Qingde
authors.initials: Q
authors.lastname: Wang
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Zhong
authors.initials: Z
authors.lastname: Hua
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Jiemei
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Dandan
authors.initials: D
authors.lastname: Chen
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Jinze
authors.initials: J
authors.lastname: Wu
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Ben
authors.initials: B
authors.lastname: Lu
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: John P
authors.initials: JP
authors.lastname: Pribis
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Weihong
authors.initials: W
authors.lastname: Jiang
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Kan
authors.initials: K
authors.lastname: Yang
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: David J
authors.initials: DJ
authors.lastname: Hackam
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.). afychen@yahoo.com billiartr@upmc.edu.
authors.forename: Alex F
authors.initials: AF
authors.lastname: Chen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D018836:Inflammation Mediators / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D058426:Neointima; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057772:Vascular System Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014657:Vasculitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse
keywords: HMGBI protein; angioplasty; carotid artery injuries; hyperplasia; macrophages