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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-04-1080.
Submitted April 10, 2002
Accepted June 5, 2002
Human  -Defensin Regulates Smooth Muscle Cell Contraction
Taher Nassar, Sa'ed Akkawi, Rachel Bar-Shavit, Abdullah Haj-Yehia, Khalil Bdeir, Abu-Bakr Al-Mehdi, Mark Tarshis, and Abd Al-Roof Higazi*
Department of Clinical Biochemistry, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel
Department of Oncology, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel
School of Pharmacy, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
Department of Environmental Medicine, University of Pennsylvania, Philadelphia, PA, USA
Interdepartmental Unit, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel
Department of Clinical Biochemistry, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
* Corresponding author; email: higazi{at}mail.med.upenn.edu.
We have previously identified -defensin in association with medial smooth muscle cells (SMC) in human coronary arteries. In the present paper we report that -defensin, at concentrations below those found in pathological conditions, inhibits phenylephrine (PE)-induced contraction of rat aortic rings. Addition of 1 µM -defensin increased the EC50 of PE on denuded aortic rings from 32 to 630 nM. The effect of -defensin was dose-dependent and saturable, with a half-maximal effect at 1 µM. -defensin binds to human umbilical vein SMC in a specific manner. The presence of 1 µM -defensin inhibited the PE-mediated Ca2+ mobilization in SMC by more than 80%. The inhibitory effect of -defensin on contraction of aorta rings and Ca2+ mobilization was completely abolished by anti-low density lipoprotein receptor-related protein/2- macroglobulin receptor (LRP) antibodies as well as by the antagonist receptor-associated protein (RAP). -defensin binds directly to isolated LRP in a specific and dose-dependent manner; the binding was inhibited by RAP as will as by anti-LRP antibodies. -defensin is internalized by SMC and interacts with two intracellular subtypes of PKC involved in muscle contraction, and ß. RAP and anti-LRP antibodies inhibited the binding and internalization of -defensin by SMC and its interaction with intracellular PKCs. These observations suggest that binding of -defensin to LRP expressed in SMC leads to its internalization; Internalized -defensin binds to PKC and inhibit its enzymatic activity leading to decreased Ca2+ mobilization and SMC contraction in response to PE.
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