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J. Biol. Chem., Vol. 282, Issue 51, 37045-37052, December 21, 2007

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Cell Type-specific Functions of the Lysosomal Protease Cathepsin L in the Heart^*

Daniel Spira, Jörg Stypmann, Desmond J. Tobin^¶, Ivonne Petermann, Christian Mayer, Sascha Hagemann, Olga Vasiljeva, Thomas Günther^||, Roland Schüle^||, Christoph Peters, and Thomas Reinheckel¹

From the Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany, Medizinische Klinik und Poliklinik C (Kardiologie und Angiologie) und Zentrale Projektgruppe IVa (Kleintierdiagnostik) des Interdisziplinären Zentrums für Klinische Forschung Münster, Universitätsklinikum Münster, D-48149 Münster, Germany, ^¶Medical Biosciences, School of Life Sciences, University of Bradford, Bradford Bd7 1DP, West Yorkshire, United Kingdom, and ^||Universitäts-Frauenklinik und Zentrum für Klinische Forschung, Klinikum der Albert Ludwigs-Universität Freiburg, D-79106, Freiburg, Germany

Deficiency of the lysosomal cysteine protease cathepsin L (Ctsl) in mice results in a phenotype affecting multiple tissues, including thymus, epidermis, and hair follicles, and in the heart develops as a progressive dilated cardiomyopathy (DCM). To understand the role of Ctsl in the maintenance of regular heart morphology and function, it is critical to determine whether the DCM in Ctsl^-/- mice is primarily because of the lack of Ctsl expression and activity in the cardiomyocytes or is caused by the additional extracardiac pathologies. Cardiomyocyte-specific expression of Ctsl in Ctsl^-/- mice, using an -myosin heavy chain promoter-Ctsl transgene, results in improved cardiac contraction, normal mRNA expression of atrionatriuretic peptide, normal heart weight, and regular ultrastructure of cardiomyocytes. Epithelial expression of cathepsin L2 (CTSL2) by a K14 promoter-CTSL2-transgene resulted in rescue of the Ctsl^-/- hair loss phenotype. In these mice, cardiac atrionatriuretic peptide expression and end systolic heart dimensions were also significantly attenuated. However, cardiac contraction was not improved, and increased heart weight as well as the typical changes in lysosomal ultrastructure of Ctsl^-/- hearts persisted. Myocardial fibrosis was detected in all Ctsl^-/- mice irrespective of transgene-mediated cardiac Ctsl expression or extracardiac CTSL2 expression. Expression of collagen 1 was not enhanced in Ctsl^-/- hearts, but a reduced collagenolytic activity suggests a role for Ctsl in collagen turnover by cardiac fibroblasts. We conclude that the DCM of Ctsl^-/- mice is primarily caused by absence of the protease in cardiomyocytes, whereas the complex gross phenotype of Ctsl-deficient mice, i.e. the fur defect, results in additional stress to the heart.

Received for publication, April 25, 2007 , and in revised form, September 21, 2007.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants Re 1584/2-1/2-2 and Sonderforschungsbereich 656 MoBil (project C3). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table and Figs. S1–S2.

¹ To whom correspondence should be addressed: Institut für Molekulare Medizin und Zellforschung; Stefan Meier Strasse 17, D-79104 Freiburg, Germany. Fax: 49-761-203-9634; E-mail: thomas.reinheckel{at}uniklinik-freiburg.de.

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