Fluvastatin upregulates endothelial nitric oxide synthase activity via enhancement of its phosphorylation and expression and via an increase in tetrahydrobiopterin in vascular endothelial cells.

BACKGROUND: An HMG-CoA reductase inhibitor, fluvastatin, appears to act directly on the blood vessel wall to stabilize plaques in situ, agents that share this property have been termed vascular statins. METHODS: We investigated the effects of fluvastatin on endothelial nitric oxide synthase (eNOS) phosphorylation and expression, as well as terahydrobiopterin (BH4) metabolism, in human umbilical vein endothelial cells (HUVEC). RESULTS: Fluvastatin was observed to enhance eNOS phosphorylation at Ser-1177 and Ser-633 through the PI3-kinase/Akt and PKA pathways, respectively. Inhibition of eNOS phosphorylation using inhibitors of these pathways attenuated acute NO release in response to fluvastatin. The mRNA of GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme of the first step of de novo BH4 synthesis, as well as eNOS, was upregulated in HUVEC treated with fluvastatin. In parallel with this observation, fluvastatin increased intracellular BH4. Pre-treatment of HUVEC with the selective GTPCH inhibitor, 2,4-diamino-6-hydroxypyrimidine, reduced intracellular BH4 and decreased citrulline formation following stimulation with ionomycin. Furthermore, the potentiating effect of fluvastatin was reduced by limiting the cellular availability of BH4. CONCLUSIONS: Our data demonstrate that fluvastatin phosphorylates and activates eNOS, and increases eNOS expression in vascular endothelial cells. In addition to modulating eNOS, fluvastatin potentiates GTPCH gene expression and BH4 synthesis, thereby increasing NO production and preventing relative shortages of BH4.

Comparative study between high-dose fluvastatin and low-dose fluvastatin and ezetimibe with regard to the effect on endothelial function in diabetic patients.

It is well established that statins improve the prognosis of patients with coronary artery disease. However, it is still unclear whether the protective effects of statins relate to lipid lowering alone or whether other pleiotropic effects may contribute. Thus, we compared the endothelial function among two groups of diabetic patients treated with fluvastatin 60 mg (F60) or fluvastatin 20 mg combined with ezetimibe 10 mg (F20/E10). The endothelial function was evaluated by measuring flow-mediated vasodilatation (FMD) at baseline and follow-up at 10 weeks. Similar improvements in FMD were observed in the two groups. The reduction in low-density lipoprotein cholesterol (LDL-C) was less pronounced in the F60 group, compared with the F20/E10 group. A significant reduction in remnant-like lipoprotein particles cholesterol (RLP-C) was observed in the F20/E10 group, but not in the F60 group. A correlation between the observed reduction in LDL-C or RLP-C and the improvement in FMD was observed in F20/E10 group. These results suggest that high-dose fluvastatin might have pleiotropic effects of potential clinical benefit, and that the combination of ezetimibe with a reduced dose of fluvastatin may also significantly improve endothelial function with reduction of LDL-C and RLP-C.

An ACTH-secreting pituitary adenoma within the sphenoid sinus.

A 68-year-old woman developed Cushingoid features three months prior to admission. She was found to have a markedly elevated plasma ACTH-cortisol level. Magnetic resonance imaging (MRI) revealed a mass in the left sphenoidal sinus, which had become enlarged to a point where it could not be removed by transsphenoidal surgery. We decided to proceed with radiation therapy to shrink the tumor. However, it was ineffective. Despite a reduction in serum cortisol levels using metyrapone, she died of septic shock. We describe a rare case of an ACTH-secreting pituitary adenoma within the sphenoid sinus.

Telmisartan inhibits cytokine-induced nuclear factor-kappaB activation independently of the peroxisome proliferator-activated receptor-gamma.

Telmisartan is an angiotensin-II type 1 receptor (AT1R) blocker, currently used to treat patients with hypertension. Telmisartan, in addition to its effect on AT1R, is thought to activate the nuclear transcription factor, peroxisome proliferator-activated receptor-gamma (PPAR gamma), thereby acting as a partial PPAR gamma agonist. This study was conducted to examine whether telmisartan might suppress cytokine-induced inflammatory signaling in vascular endothelial cells, thereby attenuating cellular inflammation possibly by PPAR gamma activation. Telmisartan caused a dose-dependent suppression of the tumor necrosis factor-alpha (TNFalpha)-induced activation of nuclear factor (NF)-kappaB in vascular endothelial cells in this study. The PPAR gamma antagonist, GW9662, did not influence the inhibitory effect of telmisartan on NF-kappaB activation. The thiazolidinediones neither influenced TNFalpha-induced NF-kappaB activation nor influenced the inhibitory effect of telmisartan in this process. Telmisartan dose dependently diminished the TNFalpha-induced gene expression of VCAM-1, and GW9662 did not attenuate this effect. Thus, telmisartan inhibits the cytokine-induced expression of the VCAM-1 gene by blocking NF-kappaB activation independently of PPAR gamma activation. Although the mechanism by which this occurs remains unclear, our findings suggest that telmisartan-induced anti-inflammatory effects might have favorable effects on vasculature in hypertensive patients.