PT  - JOURNAL ARTICLE
AU  - Céline Dubuis
AU  - Laurence May
AU  - Florian Alonso
AU  - Ludmila Luca
AU  - Ioanna Mylonaki
AU  - Paolo Meda
AU  - Florence Delie
AU  - Olivier Jordan
AU  - Sébastien Déglise
AU  - Jean-Marc Corpataux
AU  - François Saucy
AU  - Jacques-Antoine Haefliger
TI  - Atorvastatin-Loaded Hydrogel Affects the Smooth Muscle Cells of Human Veins
AID  - 10.1124/jpet.113.208769
DP  - 2013 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 574--581
VI  - 347
IP  - 3
4099  - http://jpet.aspetjournals.org/content/347/3/574.short
4100  - http://jpet.aspetjournals.org/content/347/3/574.full
SO  - J Pharmacol Exp Ther2013 Dec 01; 347
AB  - 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.