Copyright © 2005, European Society of Cardiology
Protein kinase C epsilon mediates angiotensin II-induced activation of β1-integrins in cardiac fibroblasts
aDepartment of Medicine-Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany
bDepartment of Internal Medicine, Hannover Medical School, Hannover, Germany
cMax Planck Institute for Experimental Endocrinology, Hannover, Germany
dDepartment of Biomedical Sciences, University of Modena and Reggio Emilia, Italy
* Corresponding author. Tel.: +49 30 4593 2413; fax: +49 30 4593 2415. Email address: graf{at}dhzb.de
Objective: Angiotensin II (AII) promotes cardiac fibrosis by increased extracellular matrix production and enhanced interaction of matrix proteins with their cellular receptors, including integrins. AII and other growth factors augment β1-integrin-dependent adhesion and spreading by "inside-out signaling" without affecting the total number of integrin receptors. "Inside-out signaling" involves specific signaling pathways, including protein kinase C (PKC), leading to activation of β1-integrins. In the present study we investigated the mechanisms involved in AII-increased adhesion of adult rat cardiac fibroblasts (CFBs), obtained from Sprague–Dawley rats, to collagen I mediated by β1-integrin.
Methods and results: Treatment of CFBs with AII induced a concentration-dependent increase in adhesion to collagen I (2.2-fold, p<0.01) within 3–6 h of treatment. This effect was mediated by β1-integrin via the angiotensin AT1 receptor and was significantly reduced by protein kinase C inhibition. AII significantly induced phosphorylation of PKC epsilon (PKC
), which is involved in β1-integrin-dependent adhesion and motility, and phosphorylation of the cytoplasmatic tail of β1-integrin at threonine 788/789, required for adhesion. Phosphorylation of β1-integrin and an increase in adhesion was also induced by L-
-phosphatidylinositol-3,4,5-triphosphate (L--PIP3), an activator of endogeneous PKC. AII failed to increase adhesion in myofibroblasts obtained from PKC (–/–) mice, but not in cells obtained from control mice. Co-immunoprecipitation and double immunofluorescence demonstrated that AII induced a close association of PKC with β1-integrin in CFBs.
Conclusion: The present study demonstrates that AII increased β1-integrin-dependent adhesion to collagen I in cardiac fibroblasts by inside-out signaling via PKC and phosphorylation of the cytoplasmatic tail of the β1-integrin.
KEYWORDS Angiotensin II; Integrin; Collagen; Protein kinase C
Time for primary review 32 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. K. Thodeti, B. Matthews, A. Ravi, A. Mammoto, K. Ghosh, A. L. Bracha, and D. E. Ingber TRPV4 Channels Mediate Cyclic Strain-Induced Endothelial Cell Reorientation Through Integrin-to-Integrin Signaling Circ. Res., May 8, 2009; 104(9): 1123 - 1130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Palaniyandi, L. Sun, J. C. B. Ferreira, and D. Mochly-Rosen Protein kinase C in heart failure: a therapeutic target? Cardiovasc Res, May 1, 2009; 82(2): 229 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Legate and R. Fassler Mechanisms that regulate adaptor binding to {beta}-integrin cytoplasmic tails J. Cell Sci., January 15, 2009; 122(2): 187 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bourd-Boittin, H. Le Pabic, D. Bonnier, A. L'Helgoualc'h, and N. Theret RACK1, a New ADAM12 Interacting Protein: CONTRIBUTION TO LIVER FIBROGENESIS J. Biol. Chem., September 19, 2008; 283(38): 26000 - 26009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Graf Pulmonary hyperplasia and the two sides of PKC{zeta} Cardiovasc Res, June 1, 2008; 78(3): 409 - 410. [Full Text] [PDF]
|
|
|
|
|
|
L. Huang, H.-C. Cheng, R. Isom, C.-S. Chen, R. A. Levine, and B. U. Pauli Protein Kinase C{epsilon} Mediates Polymeric Fibronectin Assembly on the Surface of Blood-borne Rat Breast Cancer Cells to Promote Pulmonary Metastasis J. Biol. Chem., March 21, 2008; 283(12): 7616 - 7627. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Lubrano, F. Soscia, M. Elli, F. Ventriglia, C. Raggi, E. Travasso, S. Scateni, V. Di Maio, P. Versacci, R. Masciangelo, et al. Renal and Cardiovascular Effects of Angiotensin-Converting Enzyme Inhibitor Plus Angiotensin II Receptor Antagonist Therapy in Children With Proteinuria Pediatrics, September 1, 2006; 118(3): e833 - e838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Stanisavljevic, T. Ignjatovic, P. A. Deddish, V. Brovkovych, K. Zhang, E. G. Erdos, and R. A. Skidgel Angiotensin I-Converting Enzyme Inhibitors Block Protein Kinase C{epsilon} by Activating Bradykinin B1 Receptors in Human Endothelial Cells J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1153 - 1158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Hein Angiotensin II and cell-matrix adhesion: PKC{varepsilon} is essential Cardiovasc Res, July 1, 2005; 67(1): 6 - 8. [Full Text] [PDF]
|
|