TGF-beta1 improves cardiac performance via up-regulation of laminin receptor 37/67 in adult ventricular cardiomyocytes.
TGF-beta1 plays an important role in cardiac fibrosis, apoptosis, induction of hypertrophy and contractile dysfunction. This study investigates whether TGF-beta1 plays a role in laminin receptor 37/67 (37/67 LR)-dependent regulation of cardiac performance. Therefore, isolated adult cardiomyocytes were stimulated with TGF-beta1, 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-beta1-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-beta1 and the relationship to distress score and lung wet weight-to-body weight was analysed. TGF-beta1 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-beta1-dependent increase in 37/67 LR expression. TGF-beta1 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-beta1 on basal cell shortening. In transgenic mice over-expressing TGF-beta1 a strong induction of laminin receptor expression attenuated the severeness of the mice' symptoms. This study shows a new and protective role of TGF-beta1-dependent up-regulation of the 37/67 LR in cardiomyocytes in cardiac remodelling with increased laminin expression.
Wenzel
Sibylle
S
Institute of Physiology, Justus-Liebig-University, Giessen, Germany. sibylle.wenzel@ugcvr.de
Henning
Kirsten
K
Habbig
Andreas
A
Forst
Svenja
S
Schreckenberg
Rolf
R
Heger
Jacqueline
J
Maxeiner
Hagen
H
Schlüter
Klaus-Dieter
KD
D000367:Age Factors; D000818:Animals; D002478:Cells, Cultured; D004719:Endomyocardial Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006352:Heart Ventricles / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017474:Receptors, Laminin / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D017474:Receptors, Laminin; D053773:Transforming Growth Factor beta1; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse