Prostaglandin E1 In Rats Research Articles

Prostaglandin E1 Attenuates Pulmonary Artery Remodeling by Activating Phosphorylation of CREB and the PTEN Signaling Pathway

The depletion of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and phosphatase and tensin homolog (PTEN) is the critical mediator of pulmonary arterial hypertension (PAH). We hypothesized that the activation of phosphorylated CREB (pCREB) and PTEN could inhibit the AKT signaling pathway to attenuate pulmonary arterial remodeling in rats with monocrotaline-induced PAH. We observed decreased PTEN and pCREB in idiopathic PAH versus control tissue. We reduced PTEN using small interfering RNA in human control pulmonary arterial smooth muscle cells (PASMCs) and observed an increase in pAKT. Consistent with PTEN knockdown in PASMCs, prostaglandin E1 (PGE1) induced pCREB expression to stimulate PTEN protein expression and inhibited pAKT in a time- and dose-dependent manner. The enhanced proliferation and migration of PASMCs following PTEN knockdown were significantly inhibited by PGE1 treatment. The PGE1-induced elevation of PTEN expression in PTEN-depleted PASMCs was decreased by the application of a PKA inhibitor and a CBP-CREB interaction inhibitor. Supplementation with a novel emulsion composition comprising PGE1 in rats with monocrotaline-induced PAH prevented pulmonary arterial remodeling and improved hemodynamics via the induced expression of PTEN. We conclude that PGE1 recruits pCREB/PTEN to decrease the migration and proliferation of PASMCs associated with PAH. This finding elucidates a relevant underlying mechanism of the PGE1/CREB/PTEN signaling pathway to prevent progressive PAH.

Influence of pregnancy on the febrile response to intracerebroventricular administration of PGE1 in rats.

Rats have an attenuated or absent febrile response to exogenous pyrogen (e.g., bacterial endotoxin) and endogenous pyrogen (e.g., interleukin-1 beta) near term of pregnancy. The present experiments have been carried out on 19 nonpregnant and 18 time-bred pregnant Long-Evans rats to investigate the febrile response to intracerebroventricular (ICV) administration of prostaglandin E1 (PGE1). Each rat was anesthetized, a biotelemetry device was placed in the peritoneal cavity for measurement of body core temperature (Tbc), and guide cannulas were placed above the lateral cerebral ventricles for ICV injection of PGE1. At least 6 days were allowed to lapse between surgery and the experiments. ICV injection of 0.2 micrograms PGE1 produced significant increases in Tbc in both nonpregnant and pregnant animals (day 19 of gestation). The increase in Tbc as well as the fever index, however, were significantly attenuated in the pregnant compared with the nonpregnant rats. Vehicle had no effect on Tbc or fever index in either group of animals. The attenuated febrile response to PGE1 in the pregnant rats may have resulted from a pregnancy-related activation of endogenous antipyretics and/or impaired thermoregulatory effector mechanisms.