Angiotensin converting enzyme inhibitors block mitogenic signalling pathways in rat cardiac fibroblasts

We studied the effects of angiotensin converting enzyme (ACE) inhibitors on angiotensin II (Ang II) induced growth related signalling pathways in neon atal rat cardiac fibroblasts. In BrdU proliferation assays, Ang II (10(-9)- 10(-7) M) stimulated cardiac fibroblast growth in a dose-dependent fashion (maximum at 10(-7) M, 5.22 +/- 0.01-fold, n = 9). 2-2-(1-(ethoxycarbonyl)-3 -phenylpropyl)[amino-oxopropyl]-6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoli ne-3 carboxylic acid (moexiprilat) led to a dose-dependent inhibition of th e Ang II induced cardiac fibroblast growth. A less pronounced effect on cel lular proliferation was seen with the ACE inhibitor enalaprilat. To elucida te the mechanisms involved in this direct antiproliferative effect of ACE i nhibitors in cardiac fibroblasts, we studied the activation of mitogen-acti vated protein kinases [MAPKs: extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38-MAPK] and JAK/STAT (janus kinases/signal transducer and activator of transcription) signal transduction pathways. Ang II (10-7 M) c aused an increase in MAPKs activity with an increased phosphorylation of ER K1/2 (1.7-fold) and p38-MAPK (3.6-fold). This effect was completely inhibit ed by moexiprilat (10(-7) M) and enalaprilat (10(-7) M). Stimulation with A ng II (10(-7) M) also led to an increased phosphorylation of STAT3, which i s one of the key effector proteins in the JAK/STAT signalling pathway. This effect was also completely inhibited by moexiprilat (10(-7) M) and enalapr ilat (10(-7) M). These data show that the ACE inhibitors moexiprilat and en alaprilat inhibit Ang II induced proliferation of cardiac fibroblasts accor ding to their relative potency of ACE inhibition in vitro. This novel effec t of ACE inhibitors is accompanied by blocking the Ang LI induced activatio n of several intracellular signal transduction pathways (ERK1/2, p38-MAPK a nd STAT3).