ALTERED EXPRESSION OF PDE1 AND PDE4 CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE ISOFORMS IN 7-OXO-PROSTACYCLIN-PRECONDITIONED RAT-HEART

M.M. KOSTIC, S. ERDOGAN, G. RENA, G. BORCHERT, B. HOCH, S. BARTEL, G. SCOTLAND, E. HUSTON, M.D. HOUSLAY AND E.-G. KRAUSE. Altered Expression of PDE1 and PDE4 Cyclic Nucleotide Phosphodiesterase Isoforms in 7-ox oprostacyclin-preconditioned Rat Heart. Journal of Molecular and Cellu lar Cardiology (1997) 29, 3135-3146. The stable prostacyclin derivativ e, 7-oxo-prostacyclin, exhibits a delayed, long-lasting cardioprotecti ve effect, which is accompanied by an increase in cyclic nucleotide ph osphodiesterase (PDE) activities restricted to the Ca2+-calmodulin-dep endent (PDE1) and cyclic AMP-specific phosphodiesterase (PDE4) activit ies, Mammalian PDEs form a large multigene family with differential ex pression occurring in a cell-and tissue-specific manner, The aim of th is study was to identify which isoforms of PDE1 and PDE4 are present i n the hearts of control and 7-oxo-prostacyclin treated rats, Using RT- PCR analysis, we were able to identify in control rat hearts transcrip ts for PDE1C, but not for either PDE1A or PDE1B within the three-gene PDE1 family. Within the four-gene PDE4 family we detected, by generic RT-PCR analysis, transcripts for PDE4A, PDE4B and PDE4D, but not PDE4C . Using RT-PCR primers for specific splice variants, we identified tra nscripts for PDE4B1, PDE4B2, PDE4B3, PDE4D1, PDE4D2 and PDE4D3 in hear ts from the control animals, Immunoblotting of hearts from the control animals for PDE4 forms allowed us to identify a 98-kDa PDE4A species, 68-kDa band representing PDE4D1/2 and a 95-kDa species indicative of PDE4D3. In the hearts of treated animals, 48 h after a single 50 mu g/ kg dose of 7-oxo-prostacyclin, a profound increase in transcript level s was seen for both PDE1C and PDE4B3 together with a slight elevation for PDE4B1. No change in PDE4A transcripts occurred, which was consist ent with a lack of change indicated in immunoblotting analyses. In con trast, 7-oxo-prostacyclin treatment caused decrease in transcript leve ls for PDE4D, which was confirmed by immunoblotting and shown to be du e to a reduction in the levels of PDE4D3 and also in PDE4D1/D2. Thus, treatment of animals with 7-oxoprostacyclin initiated profound isoform -specific changes in PDE expression in the myocardium which, presumabl y, underpin the increased PDE activity. (C) 1997 Academic Press Limite d.