Matrix metalloproteinase inhibitors in angioplasty restenosis- Pharmacological and gene transfer approaches

The injury response associated with coronary angioplasty causes 25-50% of patients to develop restenosis at the site of their original lesion, due to the migration and proliferation of smooth muscle cells and failure of compensatory expansion of the arterial wall. Cell migration across matrix boundaries is a major component in the formation of neointimal hyperplasia following vascular injury, and is dependent on the alteration of the proteolytic balance within the arterial wall towards matrix breakdown. This study investigated the hypothesis that this change is mediated in part by the matrix metalloproteinases, (MMPs) and might be prevented by their inhibition, either by pharmacological means or by their natural inhibitors the tissue inhibitors of metalloproteinases (TIMPs). Initial studies of a pharmacological inhibitor, CT1746, showed no reduction in neointimal hyperplasia after balloon injury in the rat carotid artery and highlighted problems with reliable delivery of this compound. Adenoviral and herpes gene transfer approaches were, therefore, developed and characterized in detail both in vivo and in vitro using a marker gene. A novel adenoviral vector, Av1.TIMP1, containing the TIMP1 cDNA was characterized, purified, and propagated. An increase in expression of biologically active and immunoreactive TIMP1 was seen in vitro in response to infection of smooth muscle cells (SMCs) with Av1 .TIMP1. Infection of SMCs with Av1 .TIMP1 reduced SMC invasion in vitro by 27% compared to control virally infected cells. The adenoviral vector was delivered to the rat carotid artery following balloon injury and four days later immunoreactive protein was identified and migration of smooth muscle cells reduced by 60%. The transmural expression of TIMP1 was associated with a 30% reduction in neointimal area two weeks after angioplasty. These studies support the hypothesis that arterial balloon injury involves MMP-dependent smooth muscle cell migration which can be attenuated in vivo by adenoviral gene transfer of TIMP1