XXXX alpha-defensin regulates smooth muscle cell contraction: a role for low-density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor.

@entity1 @entity541 @entity8993 @entity7131 @entity35
We have previously identified alpha-defensin in association with medial smooth muscle cells (SMCs) in @entity1 coronary arteries. In the present paper we report that alpha-defensin, at concentrations below those found in pathological conditions, inhibits phenylephrine (PE)-induced contraction of @entity35 aortic rings. Addition of 1 microM alpha-defensin increased the half-maximal effective concentration (EC(50)) of PE on denuded aortic rings from 32 to 630 nM. The effect of alpha-defensin was dose dependent and saturable, with a half-maximal effect at 1 microM. alpha-Defensin binds to @entity1 umbilical vein SMCs in a specific manner. The presence of 1 microM alpha-defensin inhibited the PE-mediated Ca(++) mobilization in SMCs by more than 80%. The inhibitory effect of alpha-defensin on contraction of aortic rings and Ca(++) mobilization was completely abolished by anti-low-density lipoprotein receptor-related protein/alpha(2-)macroglobulin receptor ( @entity8993 ) antibodies as well as by the antagonist @entity541 ( @entity541 ). alpha-Defensin binds directly to isolated @entity8993 in a specific and dose-dependent manner; the binding was inhibited by @entity541 as well as by anti- @entity8993 antibodies. alpha-Defensin is internalized by SMCs and interacts with 2 intracellular subtypes of @entity7131 ( @entity7131 ) involved in muscle contraction, alpha and beta. @entity541 and anti- @entity8993 antibodies inhibited the binding and internalization of alpha-defensin by SMCs and its interaction with intracellular PKCs. These observations suggest that binding of alpha-defensin to @entity8993 expressed in SMCs leads to its internalization; internalized alpha-defensin binds to @entity7131 and inhibits its enzymatic activity, leading to decreased Ca(++) mobilization and SMC contraction in response to PE.
