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Human Amyloidogenic Light Chains Alter Cardiomyocyte Signaling Through Disruption of Heparan Sulfate Proteoglycan (HSPG) Complex
Author(s) -
Peng Xuyang,
Kim Eugene,
Miller Thomas,
Karamitis Gregory,
Skinner Martha,
Sawyer Douglas B.,
Connors Lawreen
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a935
Subject(s) - autocrine signalling , paracrine signalling , chemistry , syndecan 1 , microbiology and biotechnology , neuregulin 1 , heparan sulfate , signal transduction , neuregulin , endocrinology , cancer research , medicine , receptor , biology , biochemistry , glycosaminoglycan , cell
Primary (AL) amyloidosis is associated with congestive heart failure may be due to direct cardiotoxicity of amyloidogenic free light chains (LC), as well as the fibrillar deposits characteristic of this disease. Amyloidogenic proteins are known to interact with heparan sulfate proteoglycans (HSPG) such as syndecan‐4, a known regulator of autocrine and paracrine signaling via ‘co‐receptor’ activity. We hypothesized that circulating levels of human amyloidogenic LC proteins might alter cardiac paracrine signaling via such a mechanism. Methods and results LC were purified from urinary samples of patients with AL amyloidosis with and without cardiac amyloidosis. The effect of LC was examined on the HSPG syndecan‐4 and signaling by the cardioprotective paracrine growth factor neuregulin in isolated adult rat ventricular myocytes. LC from patient with cardiac amyloidosis (20 ug/ml, 24 h) suppressed neuregulin activation of myocyte PKB/Akt, decreased expression of a high molecular weight syndecan‐4 complex. Co‐IP studies suggest that LC caused dissociation of erbB4, a neuregulin receptor, from syndecan‐4. Disruption of HSPG by treatment of myocytes with heparanase III caused an effect on neuregulin signaling similar to that of LC. Conclusion These results suggest that syndecan‐4 is a co‐receptor for cardioprotective neuregulin/erbB4/Akt signaling that is disrupted by the presence of amyloidogenic LC. Further studies are needed to determine whether this is a direct or indirect effect of LC, and the role this plays in the pathogenesis of amyloid cardiomyopathy.