Effect of the statin atorvastatin on intracellular signalling by the prostacyclin receptor in vitro and in vivo

Abstract

1 Prostacyclin plays a central role within the vasculature. We have previously established that the prostacyclin receptor (IP) undergoes isoprenylation, a lipid modification obligate for its function. The aim of the current study was to investigate the effect of the hydroxy methyl glutaryl co-enzyme A reductase inhibitor atorvastatin on signalling and function of the IP expressed in mammalian whole cells and in platelets isolated from patients undergoing therapeutic intervention with atorvastatin. 2 Initially, the effect of atorvastatin on signalling by the human (h) and mouse (m) IP overexpressed in human embryonic kidney 293 cells and the hIP endogenously expressed in human erythroleukaemic 92.1.7 cells was investigated. Atorvastatin significantly reduced IP-mediated cAMP generation (IC 50 6.6-11.1 mM) and [Ca 2 þ ] i mobilization (IC 50 7.2-16.4 mM) in a concentration-dependent manner, but had no effect on signalling by the nonisoprenylated b 2 adrenergic receptor or the a or b isoforms of the human thromboxane A 2 receptor (TP). 3 Moreover, atorvastatin significantly reduced IP-mediated crossdesensitization of signalling by TPa (IC 50 10.4 mM), but not by TPb. 4 In contrast to the whole-cell data, atorvastatin therapy did not interfere with IP-mediated cAMP generation or IP-induced inhibition of TP-mediated aggregation of platelets isolated from human volunteers undergoing therapeutic intervention with atorvastatin (10-80 mg per daily dose).

No effects of atorvastatin (10mg/d or 80mg/d) on nitric oxide, prostacyclin, thromboxane and oxidative stress in type 2 diabetes mellitus patients of the DALI study

“…Nevertheless, the statistically insignificantly changed urinary excretion rates of 2,3-dinor-TxB 2 and 2,3-dinor-6-keto-PGF 1␣ , as well as their molar ratio suggest that the TxA 2 /PGI 2 homeostasis was not altered to a major extent by atorvastatin or placebo in the patients investigated. Literature reports on the effects of atorvastatin on TxA 2 [71][72][73][74][75][76][77][78][79] and PGI 2 [80][81][82][83] synthesis in diabetes are rare and contradictory, presumably because the TxA 2 and PGI 2 synthesis has not been assessed by measuring 2,3-dinor-TxB 2 and 2,3-dinor-6-keto-PGF 1␣ , respectively, as required [41] and has been performed in the present study. It is of particular interest that the urinary excretion of 8-iso-PGF 2␣ correlated considerably with that of 2,3-dinor-TxB 2 but not with the urinary excretion of 2,3-dinor-6-keto-PGF 1␣ , although 2,3-dinor-6-keto-PGF 1␣ correlated with 2,3-dinor-TxB 2 .…”

Modulation of COX‐2 expression by statins in human monocytic cells

“…Mobility shift was detected and imply the inhibition of RhoA by C3-exoenzyme. C) 50 donors showed no modification of the platelet prostacyclin receptor signaling after atorvastatin administration (40). Nevertheless, the in vivo effect of statin on the vascular prostacyclin receptor-dependent signaling needs further investigation using farneyl transferase inhibitors selectively.…”

Utilidad de la citometría de flujo para valorar el efecto de la atorvastatina sobre la función plaquetaria y la movilización del Ca2+ en pacientes hiperlipémicos

“…Uno de tales mecanismos es la activación de la vía de las fosfolipasas C y A 2 que, a su vez, movilizan los depósitos internos del ión Ca 2+ que, junto a la entrada del calcio extracelular y la activación de la proteincinasa C, inicia la exposición de receptores del fibrinógeno y la reacción de secreción plaquetaria 29 . Los resultados del presente estudio indican que la atorvastatina normaliza la cinética del calcio libre citoplasmático intraplaquetario, lo que coincide, en general, con lo comunicado por otros autores que han utilizado técnicas diferentes 30 . En cuanto a la capacidad de las plaquetas para recuperar su concentración inicial de calcio después de ser activadas con trombina (indicada por el valor de la pendiente m de la recta de regresión fluorescencia-tiempo), nuestros resultados muestran que es menor en los pacientes hipercolesterolémicos que en los controles.…”