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Prostaglandin F2α (PGF2α) and the Isoprostane, 8,12-iso-Isoprostane F2α-III, Induce Cardiomyocyte Hypertrophy

1998; Elsevier BV; Volume: 273; Issue: 35 Linguagem: Inglês

10.1074/jbc.273.35.22442

1083-351X

Priya Kunapuli, John A. Lawson, Joshua Rokach, Judy L. Meinkoth, Garret A. FitzGerald,

Antioxidant Activity and Oxidative Stress

Prostaglandin receptors may be activated by their cognate ligand or by free radical catalyzed isoprostanes, products of arachidonic acid peroxidation. For example, prostaglandin F 2α (PGF 2α ) causes hypertrophy of neonatal rat ventricular myocytes, via the PGF 2α receptor (FP). However, the FP may also be activated by the isoprostane, 8,12- iso -iPF 2α -III ( Kunapuli, P., Lawson, J. A., Rokach, J., and FitzGerald, G. A. (1997) J. Biol. Chem. 272, 27147–27154) . Both ligands induce myocyte hypertrophy with overlapping potencies. Interestingly, the hypertrophic effects of these two agonists on cardiomyocytes are additive. Furthermore, the preference of these two agonists for activation of intracellular signal transduction pathways differs in several respects. Thus, PGF 2α and 8,12- iso -iPF 2α -III stimulate inositol phosphate formation with EC 50 values of 50 ± 12 nm and 3.5 ± 0.6 μm, respectively. Moreover, PGF 2α causes a robust activation (∼50-fold) of Erk2, whereas 8,12- iso -iPF 2α -III has no effect. Similarly, PGF 2α causes translocation of cytosolic phospholipase A 2 and also results in a 7-fold increment in the formation of 6-keto-PGF 1α , whereas 8,12- iso -iPF 2α -III exerts no effect on this pathway. On the other hand, both agonists are equally potent in activating JNK1 and c-Jun, whereas neither activates the p38 kinase. Both PGF 2α and 8,12- iso -iPF 2α -III activate the p70S6 kinase (p70 S6K ), but not Akt, downstream of phosphatidylinositol-3-kinase (PI3K). However, both wortmannin, a PI3K inhibitor, and rapamycin, an inhibitor of p70 S6K activity, inhibit 8,12- iso -iPF 2α -III -induced myocyte hypertrophy, with IC 50 values of 60 ± 12 and 3 ± 1.7 nm, respectively, whereas neither compound abrogates the PGF 2α -mediated response. Thus, both PGF 2α and 8,12- iso -iPF 2α -III induce myocyte hypertrophy via discrete signaling pathways. Although both agonists signal via the JNK pathway to initiate changes in c-Jun-dependent gene transcription, PGF 2α preferentially activates the MEK-Erk2- cytosolic phospholipase A 2 pathway. In contrast, the PI3K-p70 S6K pathway appears to be essential for 8,12- iso -iPF 2α -III-induced myocyte hypertrophy.