The Efficacy of Systemic Doxycycline Administration as an Inhibitor of Intimal Hyperplasia after Balloon Angioplasty Arterial Injury

Abstract

Intimal hyperplasia (IH) is the most common indicator for secondary intervention in peripheral vascular disease. Matrix metalloproteinases (MMPs) play a role in IH development due to their degradation of the extracellular matrix. Doxycycline (Doxy), a member of the tetracycline family of antibiotics, is a potent MMP inhibitor. We have previously shown that Doxy inhibitsMMP activity and vascular smooth muscle cell migration invitro. We hypothesized that Doxy would decrease MMP activity invivo and inhibit the development of IH in a rodent model of vascular injury. Doxy (400mg/pellet) was delivered by a slow-release pellet implanted 3days prior to or at the time of balloon angioplasty (BA) of the common carotid artery in female rats. At 14days post-BA, intima-to-media (I:M) ratios were 0.77±0.21 and 1.04±0.32 in the Doxy treated groups, respectively, compared to 1.25±0.26 in the control group (P = not significant; n=3). Additionally, the tested dose of Doxy in either group had no inhibitory effect on membrane type 1-MMP or MMP-2 tissue levels, as measured by immunohistochemistry, or on systemic levels of MMP, as measured by total MMP serum levels using enzyme-linked immunosorbent assay. At 14days post-BA, VSMC proliferation in the injured artery was increased to Doxy treatment prior to and at the time of surgery (23.5±3.4 and 27.2±3.9%, respectively), compared to control (11.4±0.4%; n=3), as measured by proliferating cellular nuclear antigen immunostaining. In our invivo model of vascular injury, systemic Doxy administration prior to or at the time of vascular injury does not significantly hinder the progression of IH development. Additional doses and routes of administration could be examined in order to correlate therapeutic serum levels of Doxy with effective MMP inhibition in serum and arterial tissue. However, alternative drug delivery systems are needed in order to optimize therapeutic administration of targetedMMP inhibitors for the prevention of IH development.