1. Interstitial fibroblast proliferation is an elemental feature in the development of cardiac fibrosis. The effects of inhibitors of the intracellular signalling proteins, MEK, a kinase involved in the mitogen- activated protein kinase (MAPK) pathway and phosphatidylinositol 3-kinase (PI3-K), were tested on growth of cultured human cardiac fibroblasts.
2. Cardiac fibroblasts were isolated from transplant recipient myocardium and made quiescent by serum deprivation for 48 h. Cells were incubated for 24 h with the inhibitors PD 098059 (0.3-30 μmol/L) and LY294002 (1-25 μmol/L) in the presence and absence of platelet-derived growth factor-AB (PDGF-AB, 10 ng/mL). DNA synthesis was measured by [3H]-thymidine incorporation assay (20-24 h).
3. Both compounds markedly inhibited both basal and PDGF- stimulated increases in DNA synthesis in a concentration-dependent manner. Cardiac fibroblast DNA synthesis was reduced to near control levels by PD 098059, while it was inhibited completely by LY294002.
4. These results implicate the importance of MAPK and PI3-K activation in the signal transduction pathways necessary for cardiac fibroblast replication.
|Number of pages||3|
|Journal||Clinical and Experimental Pharmacology and Physiology|
|Publication status||Published - Jul 1999|
- DNA synthesis
- Protein kinase
- Signal transduction