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(Circulation Research. 2009;104:189.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Novel Role of the CXC Chemokine Receptor 3 in Inflammatory Response to Arterial Injury

Involvement of mTORC1

Johannes B.K. Schwarz, Nicolas Langwieser, Nicole N. Langwieser, Martin J. Bek, Stefan Seidl, Hans-Henning Eckstein, Bao Lu, Albert Schömig, Hermann Pavenstädt, Dietlind Zohlnhöfer

From the Deutsches Herzzentrum and 1. Medizinische Klinik (J.B.K.S., N.L., N.N.L., A.S., D.Z.), Technische Universität München, Germany; Department of Medicine (M.J.B., H.P.), Division of Nephrology and General Medicine, University Clinic of Muenster, Germany; Institute of Pathology (S.S.), and Department of Vascular Surgery (H.H.E.), Klinikum Rechts der Isar, Technische Universität München, Germany; and Ina Sue Perlmutter Laboratory (B.L.), Children’s Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Dietlind Zohlnhöfer, Med. Klinik II-Kardiologie und Pulmologie, Campus Benjamin Franklin, Charité, Hindenburgdamm 30, D-12200 Berlin, Germany. E-mail d_zohlnhoefer{at}yahoo.com

Atherosclerosis, restenosis, and posttransplant graft atherosclerosis are characterized by endothelial damage, infiltration of inflammatory cells, and proliferation of smooth muscle cells. The CXCR3-activating chemokines interferon- inducible protein 10 (IP10) and MIG (monokine induced by interferon-) have been implicated in vascular repair and remodeling. The underlying molecular mechanisms, however, remain elusive. Here, we show that wire-mediated arterial injury induced local and systemic expression of IP10 and MIG, resulting in enhanced recruitment of CXCR3⁺ leukocytes and hematopoietic progenitor cells. This was accompanied by profound activation of mammalian target of rapamycin complex (mTORC)1, increased reactive oxygen species production, apoptosis, and intimal hyperplasia. Genetic and pharmacological inactivation of CXCR3 signaling not only suppressed recruitment of inflammatory cells but also abolished mTORC1 activation, reduced reactive oxygen species generation, and blocked apoptosis of vascular cells, resulting in significant reduction of intimal hyperplasia in vivo. In vitro, stimulation of T cells with IP10 directly activated mTORC1 and induced generation of reactive oxygen species and apoptosis in an mTORC1-dependent manner. These results strongly indicate that CXCR3-dependent activation of mTORC1 directly links stimulation of the Th1 immune system with the proliferative response of intimal cells in vascular remodeling.

Key Words: intimal hyperplasia • inflammation • apoptosis • chemokines • mTORC1

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