title: Calpain counteracts mechanosensitive apoptosis of vascular smooth muscle cells in vitro and in vivo.
abstract: 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-degrading properties, which identifies calpain as a key regulator of mechanosensitive remodeling processes of the vascular wall.
authors.affiliation: Internal Medicine/Cardiology, Dresden University of Technology, Fetscherstrasse 76, D-01307 Dresden, Germany.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Sedding
authors.forename: Matthias
authors.initials: M
authors.lastname: Homann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Seay
authors.forename: Harald
authors.initials: H
authors.lastname: Tillmanns
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Ruediger C
authors.initials: RC
authors.lastname: Braun-Dullaeus
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002154:Calpain / Q000494:pharmacology*; D002339:Carotid Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016159:Tumor Suppressor Protein p53; D002154:Calpain