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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-04-1080.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4026-4032
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Human  -defensin regulates smooth muscle cell contraction: a
role for low-density lipoprotein receptor-related
protein/2-macroglobulin receptor
Taher Nassar,
Sa'ed Akkawi,
Rachel Bar-Shavit,
Abdullah Haj-Yehia,
Khalil Bdeir,
Abu-Bakr Al-Mehdi,
Mark Tarshis, and
Abd Al-Roof Higazi
From the Departments of Clinical Biochemistry,
Oncology, Interdepartmental Unit, and School of Pharmacy, Hadassah
University Hospital and Hebrew University-Hadassah Medical School,
Jerusalem, Israel; and the Department of Pathology and
Laboratory Medicine and Department of Environmental Medicine,
University of Pennsylvania, Philadelphia.
We have previously identified  -defensin in association with
medial smooth muscle cells (SMCs) 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 half-maximal effective concentration (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 SMCs in a specific manner. The presence of 1 µM -defensin
inhibited the PE-mediated Ca++ mobilization in SMCs by more
than 80%. The inhibitory effect of -defensin on contraction of
aortic rings and Ca++ 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 well as by
anti-LRP antibodies. -Defensin is internalized by SMCs and interacts
with 2 intracellular subtypes of protein kinase C (PKC) involved in muscle contraction, and  . RAP and anti-LRP antibodies inhibited the binding and internalization of -defensin by SMCs and its interaction with intracellular PKCs. These observations suggest that
binding of -defensin to LRP expressed in SMCs leads to its internalization; internalized -defensin binds to PKC and inhibits its enzymatic activity, leading to decreased Ca++
mobilization and SMC contraction in response to PE.
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