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IBA Publikation
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DATUM, UNTERSCHRIFT / DATE, SIGNATURE
BANK AUSTRIA CREDITANSTALT, WIEN (IBAN AT04 1100 0006 2280 0100, BIC BKAUATWW), DEUTSCHE BANK MÜNCHEN (IBAN DE16 7007 0024 0238 8270 00, BIC DEUTDEDBMUC)
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IBA Publikation, pp. 3975-3984, 2011/02/15
Benign prostatic hyperplasia (BPH) is characterized by tissue overgrowth and stromal reorganization primarily due to cellular proliferation and fibroblast-to-myofibroblast transdifferentiation. To evaluate the potential of PDE5 inhibitors like tadalafil for prevention and treatment of BPH we analyzed the role of the NO/cGMP/PDE5 pathway for cellular proliferation and transforming growth factor beta 1 (TGFβ1)- induced fibroblast-to-myofibroblast transdifferentiation in primary prostate stromal cells (PrSC). Inhibition by tadalafil of PDE5 which is mainly expressed in the stromal compartment of the prostate reduced proliferation of PrSCs and to a lesser extent of primary prostate basal epithelial cells. Attenuated proliferation due to elevated intracellular cGMP levels was confirmed by inhibition of the cGMP dependent protein kinase G by its inhibitor KT2358. Moreover, tadalafil strongly attenuated TGFβ1- induced fibroblast-to-myofibroblast transdifferentiation. The inhibitory effect on transdifferentiation was also observed after siRNA-mediated PDE5 knockdown. As confirmed by the MEK1 inhibitor PD98059 this effect was mediated via MEK1 signaling. We conclude that BPH patients might benefit from adjuvant therapies with PDE5 inhibitors that inhibit stromal enlargement due to cell proliferation as well as TGFβ1- induced transdifferentiation processes.
Keywords: Benign-prostatic-hyperplasia Fibroblast-to-myofibroblast-transdifferentiation Lower-urinary-tract -symptoms PDE5 proliferation tadalafil