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(Circulation Research. 2009;105:973.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Induction of the CXC Chemokine Interferon--Inducible Protein 10 Regulates the Reparative Response Following Myocardial Infarction

Marcin Bujak^*, Marcin Dobaczewski^*, Carlos Gonzalez-Quesada, Ying Xia, Thorsten Leucker, Pawel Zymek, Vikas Veeranna, Andrew M. Tager, Andrew D. Luster, Nikolaos G. Frangogiannis

From the Section of Cardiovascular Sciences (M.B., M.D., C.G.-Q., Y.X., T.L., P.Z., V.V., and N.G.F), Department of Medicine, Baylor College of Medicine, Houston, Tex; and Center for Immunology and Inflammatory Diseases (A.M.T. and A.D.L), Massachusetts General Hospital and Harvard Medical School, Charlestown.

Correspondence to Nikolaos G. Frangogiannis, MD, Section of Cardiovascular Sciences, One Baylor Plaza BCM620, Houston TX 77030. E-mail ngf{at}bcm.tmc.edu

Rationale: Interferon--inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T-cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response.

Objective: To study the role of IP-10 in cardiac repair and remodeling.

Methods and Results: We studied cardiac repair in IP-10-null and wild-type (WT) mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10-deficient and WT animals had comparable acute infarct size. However, the absence of IP-10 resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10^–/– hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10-null and WT mice had comparable cytokine expression, the absence of IP-10 was associated with marked alterations in the cellular content of the infarct. IP-10^–/– infarcts had more intense infiltration with CD45⁺ leukocytes, Mac-2⁺ macrophages, and -smooth muscle actin (-SMA)⁺ myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and -SMA⁺ cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis but significantly inhibited basic fibroblast growth factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices.

Conclusions: Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.

Key Words: infarction • remodeling • chemokines • fibrosis • wound healing