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(Circulation. 2009;120:617-627.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Response Gene to Complement 32, a Novel Hypoxia-Regulated Angiogenic Inhibitor

Xiaojin An, BS; Yi Jin, BS; Hongnian Guo, PhD; Shi-Yin Foo, MD, PhD; Brittany L. Cully, BA; Jiaping Wu, MD; Huiyan Zeng, PhD; Anthony Rosenzweig, MD; Jian Li, MD, PhD

From the Institute of Molecular Medicine, Peking University, Beijing, China (X.A., Y.J., J.L.), and Divisions of Cardiovascular Medicine (X.A., Y.J., H.G., S.-Y.F., B.L.C., J.W., A.R., J.L.) and Molecular and Vascular Medicine (H.Z.), Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.

Correspondence to Jian Li, MD, PhD, Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston MA 02115. E-mail JLi{at}BIDMC.Harvard.edu

Received December 9, 2008; accepted May 7, 2009.

Background— Response gene to complement 32 (RGC-32) is induced by activation of complement and regulates cell proliferation. To determine the mechanism of RGC-32 in angiogenesis, we examined the role of RGC-32 in hypoxia-related endothelial cell function.

Methods and Results— Hypoxia/ischemia is able to stimulate both angiogenesis and apoptosis. Hypoxia-inducible factor-1/vascular endothelial growth factor is a key transcriptional regulatory pathway for angiogenesis during hypoxia. We demonstrated that the increased RGC-32 expression by hypoxia was via hypoxia-inducible factor-1/vascular endothelial growth factor induction in cultured endothelial cells. However, overexpression of RGC-32 reduced the proliferation and migration and destabilized vascular structure formation in vitro and inhibited angiogenesis in Matrigel assays in vivo. Silencing RGC-32 had an opposing, stimulatory effect. RGC-32 also stimulated apoptosis as shown by the increased apoptotic cells and caspase-3 cleavage. Mechanistic studies revealed that the effect of RGC-32 on the antiangiogenic response was via attenuating fibroblast growth factor 2 expression and further inhibiting expression of cyclin E without affecting vascular endothelial growth factor and fibroblast growth factor 2 signaling in endothelial cells. In the mouse hind-limb ischemia model, RGC-32 inhibited capillary density with a significant attenuation in blood flow. Additionally, treatment with RGC-32 in the xenograft tumor model resulted in reduced growth of blood vessels that is consistent with reduced colon tumor size.

Conclusions— We provide the first direct evidence for RGC-32 as a hypoxia-inducible gene and antiangiogenic factor in endothelial cells. These data suggest that RGC-32 plays an important homeostatic role in that it contributes to differentiating the pathways for vascular endothelial growth factor and fibroblast growth factor 2 in angiogenesis and provides a new target for ischemic disorder and tumor therapies.

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Clinical Summaries
Circulation 2009 120: 543-545. [Extract] [Full Text]