Atorvastatin-loaded hydrogel affects the smooth muscle cells of human veins.
Intimal hyperplasia (IH) is the major cause of stenosis of vein grafts. Drugs such as statins prevent stenosis, but their systemic administration has limited effects. We developed a hyaluronic acid hydrogel matrix, which ensures a controlled release of atorvastatin (ATV) at the site of injury. The release kinetics demonstrated that 100% of ATV was released over 10 hours, independent of the loading concentration of the hydrogel. We investigated the effects of such a delivery on primary vascular smooth muscle cells isolated from human veins. ATV decreased the proliferation, migration, and passage of human smooth muscle cells (HSMCs) across a matrix barrier in a similar dose-dependent (5-10 µM) and time-dependent manner (24-72 hours), whether the drug was directly added to the culture medium or released from the hydrogel. Expression analysis of genes known to be involved in the development of IH demonstrated that the transcripts of both the gap junction protein connexin43 (Cx43) and plasminogen activator inhibitor-1 (PAI-1) were decreased after a 24-48-hour exposure to the hydrogel loaded with ATV, whereas the transcripts of the heme oxygenase (HO-1) and the inhibitor of tissue plasminogen activator were increased. At the protein level, Cx43, PAI-1, and metalloproteinase-9 expression were decreased, whereas HO-1 was upregulated in the presence of ATV. The data demonstrate that ATV released from a hydrogel has effects on HSMCs similar to the drug being freely dissolved in the environment.
Department of Thoracic and Vascular Surgery, University Hospital, Laboratory of Experimental Medicine, Lausanne, Switzerland (C.D., L.M., F.A., S.D., J.-M.C., F.S., J.-A.H.); School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland (L.L., I.M., F.D., O.J.); and Department of Cell Physiology and Metabolism, University of Geneva, Medical Center, Geneva, Switzerland (P.M.).
Céline
C
Dubuis
Laurence
L
May
Florian
F
Alonso
Ludmila
L
Luca
Ioanna
I
Mylonaki
Paolo
P
Meda
Florence
F
Delie
Olivier
O
Jordan
Sébastien
S
Déglise
Jean-Marc
JM
Corpataux
François
F
Saucy
Jacques-Antoine
JA
Haefliger
D000069059:Atorvastatin; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D020100:Hydrogels; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D061251:Primary Cell Culture; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014680:Veins / Q000166:cytology* / Q000187:drug effects
D017931:DNA Primers; D006538:Heptanoic Acids; D020100:Hydrogels; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin