IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II-induced hypertension.
Hypertension is a typical modern lifestyle-related disease that is closely associated with the development of cardiovascular disorders. Elevation of angiotensin II (ANG II) is one of several critical factors for hypertension and heart failure; however, the mechanisms underlying the ANG II-mediated pathogenesis are still poorly understood. Here, we show that ANG II-mediated cardiac fibrosis, but not hypertrophy, is regulated by interferon regulatory factor 3 (IRF3), which until now has been exclusively studied in the innate immune system. In a ANG II-infusion mouse model (3.0 mg/kg/d), we compared IRF3-deficient mice (Irf3(-/-)/Bcl2l12(-/-)) with matched wild-type (WT) controls. The development of cardiac fibrosis [3.95 ± 0.62% (WT) vs. 1.41 ± 0.46% (Irf3(-/-)/Bcl2l12(-/-)); P<0.01] and accompanied reduction in left ventricle end-diastolic dimension [2.89 ± 0.10 mm (WT) vs. 3.51 ± 0.15 mm (Irf3(-/-)/Bcl2l12(-/-)); P=0.012] are strongly suppressed in Irf3(-/-)/Bcl2l12(-/-) mice, whereas hypertrophy still develops. Further, we provide evidence for the activation of IRF3 by ANG II signaling in mouse cardiac fibroblasts. Unlike the activation of IRF3 by innate immune receptors, IRF3 activation by ANG II is unique in that it is activated through the canonical ERK signaling pathway. Thus, our present study reveals a hitherto unrecognized function of IRF3 in cardiac remodeling, providing new insight into the progression of hypertension-induced cardiac pathogenesis.
Department of Immunology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Kensuke
K
Tsushima
Tomoko
T
Osawa
Hideyuki
H
Yanai
Akira
A
Nakajima
Akinori
A
Takaoka
Ichiro
I
Manabe
Yusuke
Y
Ohba
Yasushi
Y
Imai
Tadatsugu
T
Taniguchi
Ryozo
R
Nagai
D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D004452:Echocardiography; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000235:genetics
C543826:Bcl2l12 protein, mouse; D018076:DNA, Complementary; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D000804:Angiotensin II; D017493:Leukocyte Common Antigens