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Calpain counteracts mechanosensitive apoptosis of vascular smooth muscle cells in vitro and in vivo
Author(s) -
Sedding Daniel G.,
Homann Matthias,
Seay Ulrike,
Tillmanns Harald,
Preissner Klaus T.,
Braun-Dullaeus Ruediger C.
Publication year - 2008
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/fj.07-8853com
Subject(s) - calpain , mechanosensitive channels , apoptosis , vascular smooth muscle , microbiology and biotechnology , neointima , in vivo , chemistry , calpastatin , biology , endocrinology , medicine , biochemistry , enzyme , restenosis , stent , receptor , ion channel , smooth muscle
Mechanical forces contribute to vascular remodeling processes. Elevated mechanical stress causes apoptosis of vascular smooth muscle cells (VSMCs) within the media. This study examined the role of the cystein protease calpain in force‐induced vascular cell apoptosis and its effect on injury‐induced vascular remodeling processes. VSMCs were exposed to cyclic tensile force in vitro , which resulted in increased p53 protein expression and transcriptional activity as well as a significant increase of apoptotic VSMCs. Apoptosis was prevented by the p53 inhibitor pifithrin and by p53 antisense oligonucleotides, indicating dependency of force‐induced apoptosis on p53. Simultaneously, calpain activity increased by mechanical stress. Prevention of calpain activation by calpeptin or antisense oligonucleotides augmented strain‐induced p53 expression and transcriptional activity, resulting in a further increase of apoptotic rate. p53 protein was directly disintegrated by activated calpain. The in vivo relevance of the findings was tested: pharmacologic inhibition of initial calpain activation augmented early apoptosis of medial VSMCs 24 h after balloon injury in a p53‐dependent manner but resulted in a marked increase in late neointima formation. We conclude that calpain counteracts mechanically induced excessive VSMC apoptosis through its p53‐de‐grading properties, which identifies calpain as a key regulator of mechanosensitive remodeling processes of the vascular wall.—Sedding, D. G., Homann, M., Seay, U., Tillmanns, H., Preissner, K. T., Braun‐Dullaeus, R. C. Calpain counteracts mechanosensitive apoptosis of vascular smooth muscle cells in vitro and in vivo. FASEB J. 22, 579–589 (2008)