Abstract
TGF-β1 plays an important role in cardiac fibrosis, apoptosis, induction of hypertrophy and contractile dysfunction. This study investigates whether TGF-β1 plays a role in laminin receptor 37/67 (37/67 LR)-dependent regulation of cardiac performance. Therefore, isolated adult cardiomyocytes were stimulated with TGF-β1, the expression of the 37/67 LR was determined and cell shortening was investigated on cells attached to a non-specific, serum-based attachment substrate or to specific, laminin-coated dishes. The role of the MAP kinases in TGF-β1-dependent induction of the 37/67 LR was examined by addition of PD98059, SB202190 and SP600125. Finally, the expression of receptor mRNA was investigated in transgenic mice constitutively over-expressing TGF-β1 and the relationship to distress score and lung wet weight-to-body weight was analysed. TGF-β1 induced a significant increase of the 37/67 LR mRNA and protein expression. The cytokine induced p38 MAP kinase and JNK, but not ERK. Inhibition of either p38 MAP kinase or JNK attenuated the TGF-β1-dependent increase in 37/67 LR expression. TGF-β1 induced a loss of cell shortening in cells attached to a non-specific substrate, but not in cells on a pre-coated laminin matrix. Inhibition of JNK attenuated the protective effect of laminin receptor up-regulation on cardiac performance. Inhibition of p38 MAP kinase attenuated the depressive effect of TGF-β1 on basal cell shortening. In transgenic mice over-expressing TGF-β1 a strong induction of laminin receptor expression attenuated the severeness of the mice’ symptoms. This study shows a new and protective role of TGF-β1-dependent up-regulation of the 37/67 LR in cardiomyocytes in cardiac remodelling with increased laminin expression.
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Acknowledgments
The authors thank Nadine Lorenz, Peter Volk, and Daniela Schreiber for excellent technical assistance. Financial support of this study by the start up fund of the JLU Giessen is gratefully acknowledged.
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395_2010_108_MOESM1_ESM.doc
Characterisation of the transgenic mouse model. Given is the division into the four quartiles based on the 37/67 LR expression. The following functional data are displayed: heart rate as beats per minute (HR bpm), systolic blood preasure (BPsys mmHg), rate pressure product (RPP mmHg/min), body weight (BW g), heart weigth (HW mg), lung wet weight (LW mg) and the ratio of heart weight to body weight (HW/BW mg/g). As parameters reflecting remodelling processe the expressions of the extracellular matrix proteins elastin, collagen, laminin, and fibonectin and of TGF-β, ANF, and MMP12 are given as x-fold expression of quartile 1. *, p<0.05 vs. quartile 1; #, p<0.05 vs. quartile 3. Supplementary material 1 (DOC 20 kb)
395_2010_108_MOESM2_ESM.ppt
mRNA Expression of Laminin and the 37/67 LR of the myocyte fraction (CMC) and the non-myocyte fraction (n-CMC) seperated fron hearts of the transgenic mice. Laminin was almost not expressed in the myocyte fraction in contrast to the non-myocyte fraction, indicating that indeed laminin is a product of non-cardiomyocytes, most likely fibroblasts. But the expression of the 37/67 LR was almost equal in both fractions Data are means±s.e.m. from n=5 mice. *, p<0.05 vs. CMC. Supplementary material 2 (PPT 39 kb)
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Wenzel, S., Henning, K., Habbig, A. et al. TGF-β1 improves cardiac performance via up-regulation of laminin receptor 37/67 in adult ventricular cardiomyocytes. Basic Res Cardiol 105, 621–629 (2010). https://doi.org/10.1007/s00395-010-0108-1
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DOI: https://doi.org/10.1007/s00395-010-0108-1