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  • Although information regarding the influence of PGE on cardi


    Although information regarding the influence of PGE2 on cardiac fibroblast cell growth is sparse, the effect of PGE2 on other cell types has been studied extensively, particularly in cancer and cancer cell lines where COX-2 is over-expressed. Constitutive high levels of COX-2 expression have been noted in colorectal, prostate and lung cancer where it contributes to epithelial cell growth, invasion and cell survival. In non-small cell lung cancer cells, Krysan et al. [19] reported that PGE2 activation of p42/44 MAPK results in cell proliferation independently of the epidermal growth factor receptor pathway. Additionally, this study also reported that the effects of PGE2 were independent of cAMP and Src, but instead, could be inhibited by protein kinase C antagonism. The authors then used an EP1/EP2 receptor antagonist to suggest a role for EP1 since these cells did not express EP2. Activation of the MAPK pathway is a known regulator of cell growth and proliferation. In one of the few papers to examine cardiac fibroblast proliferation, Olson et al. [20] examined the effect of resveratrol on angiotensin II (Ang II)-stimulated proliferation and described that proliferation of cardiac fibroblasts was dependent on activation of p42/p44 MAPK. These results are in agreement with ours. However, they did not examine which 1 646 regulatory molecules were involved and their study did not find any effects of Ang II on Akt phosphorylation. Yamamoto et al. [21] also examined the effect of p42/44 MAPK activation on cell cycle progression in NIH3T3 cells, suggesting that activation of p42/44 MAPK is required for G1 to S phase transition and that this requires AP-1 activity. Their study also demonstrated that inhibition of p42/44 MAPK activation either by the MEK inhibitor U0126 or a dominant negative MEK1 prevented S phase entry. The results of our study showed that PGE2 stimulated phosphorylation of both p42/p44 MAPK and Akt in NVF. Moreover, both the MEK inhibitor (U0126) and the PI3 kinase inhibitor (wortmannin) were able to reduce PGE2-stimulated expression of cyclin D3. We also observed that inhibition of p38 MAPK potentiates the effect of PGE2 on cyclin D3 expression, consistent with Lavoie et al.\'s [22] report that cyclin D1 transcription is negatively regulated by the p38 MAPK pathway. In a new study, it was reported that the induction of cyclin D1 by IGF-1 and FGF-2 in oligodendrocyte progenitor cells is synergistic and involves stimulation of multiple signaling pathways. Frederick et al. [23] showed that whereas FGF-2 stimulation of MAPK results in increased cyclin D1 mRNA expression, activation of the PI3 kinase pathway by IGF increases protein expression of cyclin D1 by inhibiting its proteasomal degradation and maintaining its nuclear localization. Whether such pathways are responsible for our effects in NVF is presently unknown. In conclusion, the increased proliferation of cardiac fibroblasts elicited by PGE2 is likely to have deleterious effects upon the heart. Indeed, one might anticipate increased extracellular matrix deposition which would decrease contractility and compliance. Coupled with reports from our laboratory that PGE2 also causes cardiac myocyte hypertrophy, blockade of PGE2 either at the level of prostaglandin E synthase or at the receptor level may prove beneficial.