Kunapuli P, Lawson J A, Rokach J A, Meinkoth J L, FitzGerald G A
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Biol Chem. 1998 Aug 28;273(35):22442-52. doi: 10.1074/jbc.273.35.22442.
Prostaglandin receptors may be activated by their cognate ligand or by free radical catalyzed isoprostanes, products of arachidonic acid peroxidation. For example, prostaglandin F2alpha (PGF2alpha) causes hypertrophy of neonatal rat ventricular myocytes, via the PGF2alpha receptor (FP). However, the FP may also be activated by the isoprostane, 8,12-iso-iPF2alpha-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, PGF2alpha and 8,12-iso-iPF2alpha-III stimulate inositol phosphate formation with EC50 values of 50 +/- 12 nM and 3.5 +/- 0.6 microM, respectively. Moreover, PGF2alpha causes a robust activation ( approximately 50-fold) of Erk2, whereas 8,12-iso-iPF2alpha-III has no effect. Similarly, PGF2alpha causes translocation of cytosolic phospholipase A2 and also results in a 7-fold increment in the formation of 6-keto-PGF1alpha, whereas 8,12-iso-iPF2alpha-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 PGF2alpha and 8,12-iso-iPF2alpha-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-iPF2alpha-III -induced myocyte hypertrophy, with IC50 values of 60 +/- 12 and 3 +/- 1.7 nM, respectively, whereas neither compound abrogates the PGF2alpha-mediated response. Thus, both PGF2alpha and 8,12-iso-iPF2alpha-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, PGF2alpha preferentially activates the MEK-Erk2- cytosolic phospholipase A2 pathway. In contrast, the PI3K-p70(S6K) pathway appears to be essential for 8,12-iso-iPF2alpha-III-induced myocyte hypertrophy.
前列腺素受体可被其同源配体或自由基催化的异前列腺素（花生四烯酸过氧化产物）激活。例如，前列腺素F2α（PGF2α）通过PGF2α受体（FP）导致新生大鼠心室肌细胞肥大。然而，FP也可被异前列腺素8,12-异-iPF2α-III激活（库纳普利，P.，劳森，J. A.，罗卡奇，J.，和菲茨杰拉德，G. A.（1997年）《生物化学杂志》272卷，27147 - 27154页）。两种配体诱导心肌细胞肥大的效力重叠。有趣的是，这两种激动剂对心肌细胞的肥大作用是相加的。此外，这两种激动剂在激活细胞内信号转导途径方面的偏好在几个方面有所不同。因此，PGF2α和8,12-异-iPF2α-III刺激肌醇磷酸形成的EC50值分别为50±12 nM和3.5±0.6 μM。此外，PGF2α可强烈激活Erk2（约50倍），而8,12-异-iPF2α-III则无作用。同样，PGF2α可导致胞质磷脂酶A2易位，还可使6-酮-PGF1α的形成增加7倍，而8,12-异-iPF2α-III对该途径无影响。另一方面，两种激动剂在激活JNK1和c-Jun方面效力相同，而两者均不激活p38激酶。PGF2α和8,12-异-iPF2α-III均可激活磷脂酰肌醇-3-激酶（PI3K）下游的p70S6激酶（p70(S6K)），但不激活Akt。然而，PI3K抑制剂渥曼青霉素和p70(S6K)活性抑制剂雷帕霉素均可抑制8,12-异-iPF2α-III诱导的心肌细胞肥大，IC50值分别为60±12 nM和3±1.7 nM，而这两种化合物均不能消除PGF2α介导的反应。因此，PGF2α和8,12-异-iPF2α-III均通过离散的信号通路诱导心肌细胞肥大。尽管两种激动剂均通过JNK途径发出信号以启动c-Jun依赖性基因转录的变化，但PGF2α优先激活MEK-Erk2-胞质磷脂酶A2途径。相比之下，PI3K-p70(S6K)途径似乎是8,12-异-iPF2α-III诱导心肌细胞肥大所必需的。
