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Pde4dl1  -  phosphodiesterase 4D, cAMP-specific-like 1

Rattus norvegicus

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Disease relevance of PDE3


High impact information on PDE3

  • Inhibition of these PDEs, especially with inhibitors of the PDE3 isoform, promotes vascular relaxation, particularly if the preparation of smooth muscle has been preconracted [6].
  • Clofibrate did not affect the activity of the low-Km 3',5'-cyclic AMP phosphodiesterase in norepinephrine-stimulated adipocytes [7].
  • Inhibition of PDE-3 by 20 micromol/liter of milrinone or by 200 nmol/liter of trequinsin caused a 5- to 6-fold stimulation of renin secretion that was slightly enhanced by NO synthase inhibition and moderately attenuated by NO donation [8].
  • These findings suggest that PDE-3 plays a major role for the cAMP control of renin secretion [8].
  • Because PDE-3 is a cGMP-inhibited cAMP-PDE the role of endogenous cGMP for the effects of NO was examined by the use of the specific guanylate cyclase inhibitor 1-H-(1,2,4)oxodiazolo(4,3a)quinoxalin-1-one (20 micromol) [8].

Chemical compound and disease context of PDE3


Biological context of PDE3

  • Thus, in the aorta of atherosclerosis-prone insulin-resistant cp/cp rats, PDE3A gene expression is upregulated, resulting in significantly higher PDE3 activity [9].
  • Our data are consistent with an increased role for PDE3 in regulating cAMP-dependent signaling in cp/cp VSMCs and identify PDE3 as a cellular activity potentially responsible for the phenotype of cp/cp VSMCs [10].
  • Inhibition of PDE3 with cilostamide moderately stimulated lipolysis in murine 3T3-L1 and rat adipocytes (397 +/- 25% and 235 +/- 26% of control, respectively) and markedly stimulated lipolysis in human adipocytes (932 +/- 7.6% of control) [11].
  • In general, these compounds are inactive or only weakly active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis [12].
  • From the structure-activity relationship (SAR) development of a series of compounds, it was discovered that C-3 benzyl and N-2 methyl disubstitution on the pyrazole ring gave the best combination of potency and selectivity for PDE1 and PDE5 cGMP PDEs as represented by compound 4c: PDE1, IC50 = 60 nM; PDE3, IC50 = 55,000 nM; PDE5, IC50 = 75 nM [13].

Anatomical context of PDE3

  • Compartmentalization of cAMP signaling in mesangial cells by phosphodiesterase isozymes PDE3 and PDE4. Regulation of superoxidation and mitogenesis [14].
  • Therefore, some of the cAMP-mediated increase in phosphodiesterase activity seen in L6 myoblasts is due to a protein kinase A-mediated increase in PDE3 mRNA [15].
  • AIMS/HYPOTHESIS: Cilostazol, a well-known phosphodiesterase type 3 (PDE3) inhibitor for the treatment of peripheral arterial disease, has vasodilator properties and an anti-proliferative action on the growth of vascular smooth muscle cells [16].
  • RESULTS: PDE4 inhibitors, including XT-611, but not PDE3 and PDE5 inhibitors, increased mineralized nodule formation in rat and mouse bone marrow cell cultures [17].
  • Injections of rats with dibutyryl cAMP (dbcAMP) or forskolin increased both PDE3 and PDE4 activities in aortic and femoral artery VSMC [18].

Associations of PDE3 with chemical compounds

  • Cilostamide, a PDE3-selective compound, did not affect either the antimigratory activity of forskolin or its ability to increase cAMP [19].
  • Since milrinone, an inhibitor of cAMP phosphodiesterase (PDE) 3, did not reverse the effect of leptin on glucose-induced insulin secretion, its action may be independent of PDE3 [20].
  • ISO and L-85 increased total PDE3 and PDE4 activities in cardiomyocytes, although this effect was insensitive to H89 [21].
  • These results suggested a possible involvement of NO-cAMP interaction via cGMP-mediated inhibition of PDE3 [22].
  • Guanosine 3',5'-cyclic monophosphate (cGMP) analogue 8-bromo-cGMP exerted an effect similar to NO, whereas another cGMP analogue, 8-pCPT-cGMP, which selectively activates cGMP-dependent kinase without affecting cGMP-inhibited phosphodiesterase (PDE3), had no effect [22].

Regulatory relationships of PDE3

  • These results indicate that vanadate stimulates the particulate PDE3 activity by activating mainly p44 MAPK via a PKA-dependent process, and that it differs from insulin with regard to a phosphorylation cascade of PDE3 activation [23].
  • Although PDE3 and PDE4 inhibitors activated PKA and modestly elevated cAMP levels to a similar extent, only PDE3 inhibitors suppressed MC mitogenesis (-57%) and suppressed Raf-1 kinase and ERK activity (-33 and -68%, respectively) [24].

Other interactions of PDE3

  • Indeed, PDE3 inhibitor cilostamide caused potentiation of 8-bromo-cAMP-elicited elevations of Cx43 expression that is similar to the effect of SNAP, and an elevation of intracellular cAMP was detected in SNAP-treated cells [22].
  • On the other hand, the insulin-induced activations of PDE3 and Akt were inhibited by wortmannin, suggesting involvement of the Akt activation via phosphatidylinositol 3-kinase (PI3K) in the insulin action [23].
  • The ratios of PDE3 and PDE4 mRNA to GAPDH mRNA in the heart were both approximately twofold higher in DS than in DR at 11 and 18 weeks [5].
  • cDNAs encoding PDE3 [cGMP-inhibited cyclic nucleotide phosphodiesterase (cGI PDE)] isoforms, cGIP1 and cGIP2, have been cloned from rat (R) and human (H) cDNA libraries [25].
  • PDE3 inhibitors increased phosphorylation of Raf-1 on serine 43 and serine 259 and decreased phosphorylation on serine 338; PDE4 inhibitors were without effect [24].

Analytical, diagnostic and therapeutic context of PDE3

  • With a view of understanding the potential roles of phosphodiesterase (PDE)3 in the acceleration of atherosclerosis in diabetes, we have analyzed the in vivo levels of low Km cAMP PDE3 and PDE4 activities as well as PDE3A and PDE3B mRNA in a relevant animal model [9].
  • We used the polymerase chain reaction and consensus primers designed to amplify phosphodiesterase sequences to show that L6 myoblasts also contain mRNA for a type IV low Km cAMP phosphodiesterase designated PDE3 [15].
  • This hypothesis was confirmed by in situ hybridization studies with PDE3 and PDE4 probes [26].
  • This was shown using SKF94836 (PDE3 inhibitor) which maximally inhibited membrane-bound cyclic AMP PDE activity by approximately 25-30% and by RT-PCR [27].
  • Immunoblotting experiments with PDE3-selective antisera allowed the detection of both PDE3A and PDE3B immunoreactive proteins in several rat tissues, including tissues of the cardiovascular system, in primary cultures of aortic VSMC and in an SV40 large T-antigen immortalized aortic VSMC line [28].


  1. Important role of phosphodiesterase 3B for the stimulatory action of cAMP on pancreatic beta-cell exocytosis and release of insulin. Härndahl, L., Jing, X.J., Ivarsson, R., Degerman, E., Ahrén, B., Manganiello, V.C., Renström, E., Holst, L.S. J. Biol. Chem. (2002) [Pubmed]
  2. Suppression of arterial intimal hyperplasia by cilostamide, a cyclic nucleotide phosphodiesterase 3 inhibitor, in a rat balloon double-injury model. Inoue, Y., Toga, K., Sudo, T., Tachibana, K., Tochizawa, S., Kimura, Y., Yoshida, Y., Hidaka, H. Br. J. Pharmacol. (2000) [Pubmed]
  3. Lipopolysaccharide-induced acute renal failure in conscious rats: effects of specific phosphodiesterase type 3 and 4 inhibition. Jonassen, T.E., Graebe, M., Promeneur, D., Nielsen, S., Christensen, S., Olsen, N.V. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
  4. Mesenteritis precedes vasculitis in the rat mesentery after subacute administration of a phosphodiesterase type 4 inhibitor. Mecklenburg, L., Heuser, A., Juengling, T., Kohler, M., Foell, R., Ockert, D., Tuch, K., Bode, G. Toxicol. Lett. (2006) [Pubmed]
  5. Enhanced activities and gene expression of phosphodiesterase types 3 and 4 in pressure-induced congestive heart failure. Takahashi, K., Osanai, T., Nakano, T., Wakui, M., Okumura, K. Heart and vessels. (2002) [Pubmed]
  6. Cyclic nucleotide phosphodiesterases and vascular smooth muscle. Polson, J.B., Strada, S.J. Annu. Rev. Pharmacol. Toxicol. (1996) [Pubmed]
  7. Inhibition of hormone-stimulated lipolysis by clofibrate. A possible mechanism for its hypolipidemic action. D'Costa, M.A., Angel, A. J. Clin. Invest. (1975) [Pubmed]
  8. Stimulation of renin secretion by nitric oxide is mediated by phosphodiesterase 3. Kurtz, A., Götz, K.H., Hamann, M., Wagner, C. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  9. Cyclic nucleotide phosphodiesterase 3 expression in vivo: evidence for tissue-specific expression of phosphodiesterase 3A or 3B mRNA and activity in the aorta and adipose tissue of atherosclerosis-prone insulin-resistant rats. Nagaoka, T., Shirakawa, T., Balon, T.W., Russell, J.C., Fujita-Yamaguchi, Y. Diabetes (1998) [Pubmed]
  10. Altered phosphodiesterase 3-mediated cAMP hydrolysis contributes to a hypermotile phenotype in obese JCR:LA-cp rat aortic vascular smooth muscle cells: implications for diabetes-associated cardiovascular disease. Netherton, S.J., Jimmo, S.L., Palmer, D., Tilley, D.G., Dunkerley, H.A., Raymond, D.R., Russell, J.C., Absher, P.M., Sage, E.H., Vernon, R.B., Maurice, D.H. Diabetes (2002) [Pubmed]
  11. The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis. Snyder, P.B., Esselstyn, J.M., Loughney, K., Wolda, S.L., Florio, V.A. J. Lipid Res. (2005) [Pubmed]
  12. Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity. Ahn, H.S., Bercovici, A., Boykow, G., Bronnenkant, A., Chackalamannil, S., Chow, J., Cleven, R., Cook, J., Czarniecki, M., Domalski, C., Fawzi, A., Green, M., Gündes, A., Ho, G., Laudicina, M., Lindo, N., Ma, K., Manna, M., McKittrick, B., Mirzai, B., Nechuta, T., Neustadt, B., Puchalski, C., Pula, K., Zhang, H. J. Med. Chem. (1997) [Pubmed]
  13. Synthesis and evaluation of polycyclic pyrazolo[3,4-d]pyrimidines as PDE1 and PDE5 cGMP phosphodiesterase inhibitors. Xia, Y., Chackalamannil, S., Czarniecki, M., Tsai, H., Vaccaro, H., Cleven, R., Cook, J., Fawzi, A., Watkins, R., Zhang, H. J. Med. Chem. (1997) [Pubmed]
  14. Compartmentalization of cAMP signaling in mesangial cells by phosphodiesterase isozymes PDE3 and PDE4. Regulation of superoxidation and mitogenesis. Chini, C.C., Grande, J.P., Chini, E.N., Dousa, T.P. J. Biol. Chem. (1997) [Pubmed]
  15. Protein kinase A regulation of cAMP phosphodiesterase expression in rat skeletal myoblasts. Kovala, T., Lorimer, I.A., Brickenden, A.M., Ball, E.H., Sanwal, B.D. J. Biol. Chem. (1994) [Pubmed]
  16. Inhibition of neointimal formation after balloon injury by cilostazol, accompanied by improvement of endothelial dysfunction and induction of hepatocyte growth factor in rat diabetes model. Aoki, M., Morishita, R., Hayashi, S., Jo, N., Matsumoto, K., Nakamura, T., Kaneda, Y., Ogihara, T. Diabetologia (2001) [Pubmed]
  17. Prostaglandin E2-mediated anabolic effect of a novel inhibitor of phosphodiesterase 4, XT-611, in the in vitro bone marrow culture. Miyamoto, K., Suzuki, H., Yamamoto, S., Saitoh, Y., Ochiai, E., Moritani, S., Yokogawa, K., Waki, Y., Kasugai, S., Sawanishi, H., Yamagami, H. J. Bone Miner. Res. (2003) [Pubmed]
  18. Vascular smooth muscle cell phosphodiesterase (PDE) 3 and PDE4 activities and levels are regulated by cyclic AMP in vivo. Tilley, D.G., Maurice, D.H. Mol. Pharmacol. (2002) [Pubmed]
  19. Synergistic inhibition of vascular smooth muscle cell migration by phosphodiesterase 3 and phosphodiesterase 4 inhibitors. Palmer, D., Tsoi, K., Maurice, D.H. Circ. Res. (1998) [Pubmed]
  20. Physiological increase in plasma leptin markedly inhibits insulin secretion in vivo. Cases, J.A., Gabriely, I., Ma, X.H., Yang, X.M., Michaeli, T., Fleischer, N., Rossetti, L., Barzilai, N. Diabetes (2001) [Pubmed]
  21. Negative feedback exerted by cAMP-dependent protein kinase and cAMP phosphodiesterase on subsarcolemmal cAMP signals in intact cardiac myocytes: an in vivo study using adenovirus-mediated expression of CNG channels. Rochais, F., Vandecasteele, G., Lefebvre, F., Lugnier, C., Lum, H., Mazet, J.L., Cooper, D.M., Fischmeister, R. J. Biol. Chem. (2004) [Pubmed]
  22. Nitric oxide-mediated regulation of connexin43 expression and gap junctional intercellular communication in mesangial cells. Yao, J., Hiramatsu, N., Zhu, Y., Morioka, T., Takeda, M., Oite, T., Kitamura, M. J. Am. Soc. Nephrol. (2005) [Pubmed]
  23. Orthovanadate stimulates cAMP phosphodiesterase 3 activity in isolated rat hepatocytes through mitogen-activated protein kinase activation dependent on cAMP-dependent protein kinase. Watanabe, T., Satoo, H., Kohara, K., Takami, R., Motoyashiki, T., Morita, T., Ueki, H. Biol. Pharm. Bull. (2004) [Pubmed]
  24. Differential regulation of mesangial cell mitogenesis by cAMP phosphodiesterase isozymes 3 and 4. Cheng, J., Thompson, M.A., Walker, H.J., Gray, C.E., Diaz Encarnacion, M.M., Warner, G.M., Grande, J.P. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  25. Characterization of two recombinant PDE3 (cGMP-inhibited cyclic nucleotide phosphodiesterase) isoforms, RcGIP1 and HcGIP2, expressed in NIH 3006 murine fibroblasts and Sf9 insect cells. Leroy, M.J., Degerman, E., Taira, M., Murata, T., Wang, L.H., Movsesian, M.A., Meacci, E., Manganiello, V.C. Biochemistry (1996) [Pubmed]
  26. Oocyte maturation involves compartmentalization and opposing changes of cAMP levels in follicular somatic and germ cells: studies using selective phosphodiesterase inhibitors. Tsafriri, A., Chun, S.Y., Zhang, R., Hsueh, A.J., Conti, M. Dev. Biol. (1996) [Pubmed]
  27. The role of the cyclic GMP-inhibited cyclic AMP-specific phosphodiesterase (PDE3) in regulating clonal BRIN-BD11 insulin secreting cell survival. Ahmad, M., Flatt, P.R., Furman, B.L., Pyne, N.J. Cell. Signal. (2000) [Pubmed]
  28. Expression of cyclic GMP-inhibited phosphodiesterases 3A and 3B (PDE3A and PDE3B) in rat tissues: differential subcellular localization and regulated expression by cyclic AMP. Liu, H., Maurice, D.H. Br. J. Pharmacol. (1998) [Pubmed]
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