Induction of the CXC chemokine interferon-gamma-inducible protein 10 regulates the reparative response following myocardial infarction.
BACKGROUND
Interferon-gamma-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.


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 alpha-smooth muscle actin (alpha-SMA)(+) myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and alpha-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.
Section of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, Tex., USA.
Marcin
M
Bujak
Marcin
M
Dobaczewski
Carlos
C
Gonzalez-Quesada
Ying
Y
Xia
Thorsten
T
Leucker
Pawel
P
Zymek
Vikas
V
Veeranna
Andrew M
AM
Tager
Andrew D
AD
Luster
Nikolaos G
NG
Frangogiannis
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism*; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
D000199:Actins; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D037502:Galectin 3; D054367:Receptors, CXCR3; D017493:Leukocyte Common Antigens