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(American Journal of Pathology. 2005;166:303-312.)
© 2005 American Society for Investigative Pathology

CARP, a Cardiac Ankyrin Repeat Protein, Is Up-Regulated during Wound Healing and Induces Angiogenesis in Experimental Granulation Tissue

Yubin Shi^*, Birgit Reitmaier, Johannes Regenbogen, R. Michael Slowey^*, Susan R. Opalenik^*, Eckhard Wolf, Andreas Goppelt and Jeffrey M. Davidson^*

From the Department of Pathology,^* Vanderbilt University, Nashville, Tennessee; the Department of Veterans Affairs Medical Center, Nashville, Tennessee; Institut für Molekulare Tierzucht und Biotechnologie der Ludwig-Maximilians-Universität, München, Germany; and Switch Biotech AG, Neuried, Germany

Cardiac ankyrin repeat protein (CARP) was identified by subtractive hybridization as one of a group of genes that are rapidly modulated by acute wounding of mouse skin. Quantitative RT-PCR showed that CARP was strongly induced during the first day after wounding (157.1-fold), and the high level persisted for up to 14 days. Immunohistochemistry and in situ hybridization revealed that CARP was expressed in skeletal muscle, vessel wall, hair follicle, inflammatory cells, and epidermis in the wound area. To examine the effects of CARP on wound healing, we developed an adenoviral CARP vector to treat subcutaneously implanted sponges in either rats or Flk-1^LacZ knock-in mice. Four days after infection, CARP-infected sponges in rats showed a remarkable increase in the vascular component in granulation tissue as compared to Ad-LacZ controls. This result was confirmed by CD34 immunostaining. By 7 days post-infection of sponge implants in Flk-1^LacZ knock-in mice, granulation tissue showed many more LacZ-positive cells in Ad-CARP-infected sponges than in virus controls. Ad-CARP treatment also induced neovascularization and increased blood perfusion in rabbit excisional wounds in and ischemic rat wounds. These findings indicate that CARP could play a unique role in therapeutic angiogenesis during wound healing.

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