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.
Bujak
Marcin
M
Section of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, Tex., USA.
Dobaczewski
Marcin
M
Gonzalez-Quesada
Carlos
C
Xia
Ying
Y
Leucker
Thorsten
T
Zymek
Pawel
P
Veeranna
Vikas
V
Tager
Andrew M
AM
Luster
Andrew D
AD
Frangogiannis
Nikolaos G
NG
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