Balloon dilatation of the coronary arteries is extremely effective in treating patients suffering from angina due to coronary artery disease, with an initial success rate of over 90%. However, restenosis occurs in 25-50% if patients, a process caused by injury-induced activation of smooth muscle cells (SMC) that reside in the arterial wall. After balloon injury the SMC proliferate excessively, thereby obstructing the artery and impeding blood flow. We are attempting to define the molecular basis of SMC proliferation so as to develop novel approaches to prevent restenosis based on the molecular response to injury. The first approach we are developing involves the use of gene products that can specifically target, and thereby inhibit, synthesis of mitogenic proteins. This can be achieved by transfecting cells with a gene that encodes an inhibitory factor, or one that overexpresses a mutant form of the mitogen that, with the mutation, is devoid of mitogenic effect. The second approach is to use antisense strategies. To achieve this, last year we cloned and sequenced rabbit genes encoding EGF, IGF-1, FGF, and cyclin B1. This year we have focused on cyclin B- 1, a critical element in controling progression of cells through the cell cycle. Having defined its sequence, we synthesized several antisense oligonucleotides (ODN). Unfortunately, none of these ODNs inhibited SMC proliferation. Our second experiment, focusing on cyclin B-1, was to transvect SMCs with a plasmid encoding antisense mRNA, and another encoding a mutated form of cyclin B-1 which had been shown in Xenopus eggs to inhibit progression of the cell through M phase of the cell cycle. To date, none of these approaches has succeeded in preventing SMC proliferation. However, additional studies are in progress.
NIH ExPorter
NIH ExPorter