| First Author | Stawowy P | Year | 2005 |
| Journal | Cardiovasc Res | Volume | 67 |
| Issue | 1 | Pages | 50-9 |
| PubMed ID | 15949469 | Mgi Jnum | J:106401 |
| Mgi Id | MGI:3618446 | Doi | 10.1016/j.cardiores.2005.03.002 |
| Citation | Stawowy P, et al. (2005) Protein kinase C epsilon mediates angiotensin II-induced activation of beta1-integrins in cardiac fibroblasts. Cardiovasc Res 67(1):50-9 |
| abstractText | 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 beta(1)-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 beta1-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 beta1-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 beta1-integrin via the angiotensin AT1 receptor and was significantly reduced by protein kinase C inhibition. AII significantly induced phosphorylation of PKC epsilon (PKCepsilon), which is involved in beta1-integrin-dependent adhesion and motility, and phosphorylation of the cytoplasmatic tail of beta1-integrin at threonine 788/789, required for adhesion. Phosphorylation of beta1-integrin and an increase in adhesion was also induced by l-alpha-phosphatidylinositol-3,4,5-triphosphate (l-alpha-PIP3), an activator of endogenous PKCepsilon. AII failed to increase adhesion in myofibroblasts obtained from PKCepsilon (-/-) mice, but not in cells obtained from control mice. Co-immunoprecipitation and double immunofluorescence demonstrated that AII induced a close association of PKCepsilon with beta1-integrin in CFBs. CONCLUSION: The present study demonstrates that AII increased beta1-integrin-dependent adhesion to collagen I in cardiac fibroblasts by inside-out signaling via PKCepsilon and phosphorylation of the cytoplasmatic tail of the beta1-integrin. |
