Prostaglandin F2α (PGF2α) and the isoprostane, 8,12-iso-isoprostane F2α-III, induce cardiomyocyte hypertrophy -: Differential activation of downstream signaling pathways
Prostaglandin F2α (PGF2α) and the isoprostane, 8,12-iso-isoprostane F2α-III, induce cardiomyocyte hypertrophy -: Differential activation of downstream signaling pathways
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DOI：
10.1074/jbc.273.35.22442
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发表时间：
1998-08-28
影响因子：
4.8
通讯作者：
FitzGerald, GA
中科院分区：
文献类型：
--
作者：
Kunapuli, P;Lawson, JA;FitzGerald, GA
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F-2α（PGF（2α））通过PGF（2α）受体（FP）引起新生大鼠心室肌细胞肥大。然而，FP也可以被异前列烷8,12-iso-iPF(2α)-III激活(Kunapuli, P., Lawson, J. A, Rokach, J., and FitzGerald, G. A. (1997) J. Biol. Chem 272, 27147-27154)。两种配体均以重叠的效力诱导心肌细胞肥大。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，这两种激动剂对细胞内信号转导途径激活的偏好在几个方面有所不同。因此，PGF(2α)和8,12-iso-iPF(2α)-III刺激磷酸肌醇形成，EC50值分别为50+/-12nM和3.5+/-0.6μM。此外，PGF(2 α) 会导致 Erk2 强烈激活（类似于 50 倍），而 9,12-iso-iPF(2 α)-III 则没有作用。同样，PGF(2 α) 会引起胞质磷脂酶 A 的易位，并且还会导致 6-keto-PGF(1 α) 的形成增加 7 倍，而 8,12-iso-iPF(2 α)-III 对此途径没有影响。另一方面，两种激动剂在激活 JNK1 和 c-Jun 方面具有同等效力，但都不激活 p38 激酶。 PGF(2 α) 和 8,12-iso-iPF(2 α)-III 均激活 p70S6 激酶 (p70(S6K))，但不激活磷脂酰肌醇 3 激酶 (PI3K) 下游的 Akt。然而，渥曼青霉素（一种 PI3K 抑制剂）和雷帕霉素（一种 p70(S6K) 活性抑制剂）均能抑制 8,12-iso-iPF(2 α)-III 诱导的肌细胞肥大，IC50 值分别为 60 +/- 12 和 3 +/- 1.7 nM，而两种化合物均不会消除 PGF(2 α) 介导的反应。因此，PGF(2α) 和 8,12-iso-iPF(2α)-III 均通过离散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 PGF(2α) 优先激活 MEH-Erk2-胞质磷脂酶 A(2) 途径。相反，PI3K-p70(S6K) 途径似乎对于 8,12-iso-iPF(2 α)-III 诱导的肌细胞肥大至关重要。
Prostaglandin receptors may be activated by their cognate ligand or by free radical catalyzed isoprostanes, products of arachidonic acid peroxidation. For example, prostaglandin F-2 alpha (PGF(2 alpha)) causes hypertrophy of neonatal rat ventricular myocytes, via the PGF(2 alpha) receptor (FP). However, the FP may also be activated by the isoprostane, 8,12-iso-iPF(2 alpha)-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(2 alpha) and 8,12-iso-iPF(2 alpha)-III stimulate inositol phosphate formation with EC50 values of 50 +/- 12 nM and 3.5 +/- 0.6 mu M, respectively. Moreover, PGF(2 alpha) causes a robust activation (similar to 50-fold) of Erk2, whereas 9,12-iso-iPF(2 alpha)-III has no effect. Similarly, PGF(2 alpha) causes translocation of cytosolic phospholipase A, and also results in a 7-fold increment in the formation of 6-keto-PGF(1 alpha), whereas 8,12-iso-iPF(2 alpha)-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(2 alpha) and 8,12-iso-iPF(2 alpha)-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(2 alpha)-III-induced myocyte hypertrophy, with IC50 values of 60 +/- 12 and 3 +/- 1.7 nM, respectively, whereas neither compound abrogates the PGF(2 alpha)-mediated response. Thus, both PGF(2 alpha) and 8,12-iso-iPF(2 alpha)-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(2 alpha) preferentially activates the MEH-Erk2- cytosolic phospholipase A(2) pathway. In contrast, the PI3K-p70(S6K) pathway appears to be essential for 8,12-iso-iPF(2 alpha)-III-induced myocyte hypertrophy.