title: Cell type-specific functions of the lysosomal protease cathepsin L in the heart.
abstract: 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 alpha-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.
authors.affiliation: Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Spira
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Desmond J
authors.initials: DJ
authors.lastname: Tobin
authors.forename: Ivonne
authors.initials: I
authors.lastname: Petermann
authors.forename: Christian
authors.initials: C
authors.lastname: Mayer
authors.forename: Sascha
authors.initials: S
authors.lastname: Hagemann
authors.forename: Olga
authors.initials: O
authors.lastname: Vasiljeva
authors.forename: Thomas
authors.initials: T
authors.lastname: Günther
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.forename: Christoph
authors.initials: C
authors.lastname: Peters
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D056668:Cathepsin L; D002403:Cathepsins / Q000096:biosynthesis* / Q000235:genetics; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018859:Hair Follicle / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D009929:Organ Size / Q000235:genetics; D009928:Organ Specificity / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D024723:Ventricular Myosins / Q000235:genetics
chemical_list: D024042:Collagen Type I; D011506:Proteins; C018589:lysosomal proteins; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D024723:Ventricular Myosins