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The inhibitory effect of simvastatin and aspirin on histamine responsiveness in human vascular endothelial cells.

American journal of physiology. Cell physiology (2014-01-31)
Mais Absi, Jason I Bruce, Donald T Ward
ABSTRACT

Statins and aspirin deliver well-established cardiovascular benefits resulting in their increased use as combined polypills to decrease risk of stroke and heart disease. However, the direct endothelial effect of combined statin/aspirin cotreatment remains unclear. Histamine is an inflammatory mediator that increases vascular permeability, and so we examined the effect of treating human umbilical vein endothelial cells (HUVECs) for 24 h with 1 μM simvastatin and 100 μM aspirin on histamine responsiveness. Subsequent histamine (1 μM) challenge increased intracellular calcium (Ca(2+)i) concentration, an effect that was significantly inhibited by combined simvastatin/aspirin pretreatment but not when then the compounds were given separately, even at 10-fold higher concentrations. In contrast, the Ca(2+)i mobilization response to ATP challenge (10 μM) was not inhibited by combined simvastatin/aspirin pretreatment. The H1 receptor antagonist pyrilamine significantly inhibited both histamine-induced Ca(2+)i mobilization and extracellular signal-regulated kinase (ERK) activation, whereas ranitidine (H2 receptor antagonist) was without effect. However, combined simvastatin/aspirin pretreatment failed to decrease H1 receptor protein expression ruling out receptor downregulation as the mechanism of action. Histamine-induced ERK activation was also inhibited by atorvastatin pretreatment, while simvastatin further inhibited histamine-induced vascular endothelial cadherin phosphorylation as well as altered HUVEC morphology and inhibited actin polymerization. Therefore, in addition to the known therapeutic benefits of statins and aspirin, here we provide initial cellular evidence that combined statin/aspirin treatment inhibits histamine responsiveness in HUVECs.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Histamine, ≥97.0%
Supelco
Histamine, analytical standard
Supelco
Simvastatin, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Simvastatin, ≥97% (HPLC), solid
USP
Simvastatin, United States Pharmacopeia (USP) Reference Standard
Simvastatin, European Pharmacopoeia (EP) Reference Standard
Supelco
Simvastatin, analytical standard