The inhibitory effect of simvastatin and aspirin on histamine responsiveness in human vascular endothelial cells.
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.
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; and.
Mais
M
Absi
Jason I
JI
Bruce
Donald T
DT
Ward
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology*; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology*; D017442:Histamine Agonists / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors; D000099152:Cadherin 5
D000199:Actins; D015703:Antigens, CD; D001241:Aspirin; D015820:Cadherins; D002118:Calcium; D002317:Cardiovascular Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D006632:Histamine; D017442:Histamine Agonists; D006633:Histamine Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011969:Receptors, Histamine H1; D019821:Simvastatin; D000099152:Cadherin 5
HUVEC; cadherin; endothelium; histamine; intracellular calcium