Cargando…
Interstitial remodeling in β1-adrenergic receptor transgenic mice
BACKGROUND: Inhibition of proteolytic MMP activity could be a therapeutic approach to prevent ventricular dilatation by diminishing collagen matrix turnover and interstitial fibrosis. We investigated the time-course of MMP/TIMP activity during transition from hypertrophy to ventricular dilatation in...
Autores principales: | , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Steinkopff-Verlag
2006
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779411/ https://www.ncbi.nlm.nih.gov/pubmed/17122889 http://dx.doi.org/10.1007/s00395-006-0635-y |
_version_ | 1782174392379244544 |
---|---|
author | Seeland, U. Selejan, S. Engelhardt, S. Müller, P. Lohse, M. J. Böhm, M. |
author_facet | Seeland, U. Selejan, S. Engelhardt, S. Müller, P. Lohse, M. J. Böhm, M. |
author_sort | Seeland, U. |
collection | PubMed |
description | BACKGROUND: Inhibition of proteolytic MMP activity could be a therapeutic approach to prevent ventricular dilatation by diminishing collagen matrix turnover and interstitial fibrosis. We investigated the time-course of MMP/TIMP activity during transition from hypertrophy to ventricular dilatation in transgenic mice with myocyte overexpression of the human β1-adrenergic receptor (β1TG). These β1TG mice were studied at 3 (normal function), 5 (hypertrophy) and 12 (ventricular dilatation) months of age compared to age-matched controls (WT). METHODS: Picro Sirius red staining and real-time PCR were performed for total collagen and for collagen type I and III quantification, respectively. MMP-activity assays (zymography), immunoblotting and real-time PCR experiments were done for gelatinase- (MMP-2, -9), collagenase- (MMP-1, -13), membrane-type MMP- (MT1- MMP; MMP-14) and TIMP expression measurements. To investigate β1-integrin activity, integrin-linked kinase (ILK) expression was measured by immunoblotting. RESULTS: Compared to WT with normal cardiac function, interstitial collagen type I and III mRNA and protein expression increased 3.6-fold in β1TG at 5 months of age with moderate fibrosis and cardiomyocyte hypertrophy and 17-fold in β1TG at 12 months of age with severe fibrosis and ventricular dilatation. Protein expression of the collagenases MMP-1 and -13 as well as the gelatinase proMMP-2 increased in the β1TG group with cardiac hypertrophy. Maximal activity of the gelatinase MMP-2 (3.5-fold vs.WT) was measured in β1TG at 12 months of age with severe fibrosis and ventricular dilatation, accompanied by coexpression of MT1- MMP (3.8-fold vs.WT) colocalized to the cell membranes. CONCLUSION: These data provide evidence that sympathetic overactivation can trigger interstitial matrix remodeling and fibrosis by induction of MMP/TIMP activity. In particular gelatinolytic MMP-2 activity accompanies ventricular dilatation and the development of heart failure. |
format | Text |
id | pubmed-2779411 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2006 |
publisher | Steinkopff-Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-27794112009-11-23 Interstitial remodeling in β1-adrenergic receptor transgenic mice Seeland, U. Selejan, S. Engelhardt, S. Müller, P. Lohse, M. J. Böhm, M. Basic Res Cardiol Original Contribution BACKGROUND: Inhibition of proteolytic MMP activity could be a therapeutic approach to prevent ventricular dilatation by diminishing collagen matrix turnover and interstitial fibrosis. We investigated the time-course of MMP/TIMP activity during transition from hypertrophy to ventricular dilatation in transgenic mice with myocyte overexpression of the human β1-adrenergic receptor (β1TG). These β1TG mice were studied at 3 (normal function), 5 (hypertrophy) and 12 (ventricular dilatation) months of age compared to age-matched controls (WT). METHODS: Picro Sirius red staining and real-time PCR were performed for total collagen and for collagen type I and III quantification, respectively. MMP-activity assays (zymography), immunoblotting and real-time PCR experiments were done for gelatinase- (MMP-2, -9), collagenase- (MMP-1, -13), membrane-type MMP- (MT1- MMP; MMP-14) and TIMP expression measurements. To investigate β1-integrin activity, integrin-linked kinase (ILK) expression was measured by immunoblotting. RESULTS: Compared to WT with normal cardiac function, interstitial collagen type I and III mRNA and protein expression increased 3.6-fold in β1TG at 5 months of age with moderate fibrosis and cardiomyocyte hypertrophy and 17-fold in β1TG at 12 months of age with severe fibrosis and ventricular dilatation. Protein expression of the collagenases MMP-1 and -13 as well as the gelatinase proMMP-2 increased in the β1TG group with cardiac hypertrophy. Maximal activity of the gelatinase MMP-2 (3.5-fold vs.WT) was measured in β1TG at 12 months of age with severe fibrosis and ventricular dilatation, accompanied by coexpression of MT1- MMP (3.8-fold vs.WT) colocalized to the cell membranes. CONCLUSION: These data provide evidence that sympathetic overactivation can trigger interstitial matrix remodeling and fibrosis by induction of MMP/TIMP activity. In particular gelatinolytic MMP-2 activity accompanies ventricular dilatation and the development of heart failure. Steinkopff-Verlag 2006-11-24 2007-03 /pmc/articles/PMC2779411/ /pubmed/17122889 http://dx.doi.org/10.1007/s00395-006-0635-y Text en © Steinkopff-Verlag 2006 |
spellingShingle | Original Contribution Seeland, U. Selejan, S. Engelhardt, S. Müller, P. Lohse, M. J. Böhm, M. Interstitial remodeling in β1-adrenergic receptor transgenic mice |
title | Interstitial remodeling in β1-adrenergic
receptor transgenic mice |
title_full | Interstitial remodeling in β1-adrenergic
receptor transgenic mice |
title_fullStr | Interstitial remodeling in β1-adrenergic
receptor transgenic mice |
title_full_unstemmed | Interstitial remodeling in β1-adrenergic
receptor transgenic mice |
title_short | Interstitial remodeling in β1-adrenergic
receptor transgenic mice |
title_sort | interstitial remodeling in β1-adrenergic
receptor transgenic mice |
topic | Original Contribution |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779411/ https://www.ncbi.nlm.nih.gov/pubmed/17122889 http://dx.doi.org/10.1007/s00395-006-0635-y |
work_keys_str_mv | AT seelandu interstitialremodelinginb1adrenergicreceptortransgenicmice AT selejans interstitialremodelinginb1adrenergicreceptortransgenicmice AT engelhardts interstitialremodelinginb1adrenergicreceptortransgenicmice AT mullerp interstitialremodelinginb1adrenergicreceptortransgenicmice AT lohsemj interstitialremodelinginb1adrenergicreceptortransgenicmice AT bohmm interstitialremodelinginb1adrenergicreceptortransgenicmice |