ViewpointViewpoint Overcoming restenosis with sirolimus: from alphabet soup to clinical reality
Section snippets
What is restenosis?
Restenosis is a reduction in luminal size after an intraarterial procedure and is a maladaptive response of the vasculature to injury. Angiographically significant restenosis is defined as a reduction of lumen size of greater than 50%, or a greater than 30% reduction from initial post-procedure lumen size.3 The rate of restenosis varies depending on the percutaneous approach used and the type of coronary lesions treated. Several studies have documented a post-PTCA restenosis rate of 30–40% at
Mechanism of neointimal formation
Growth factors and cytokines are believed to be major stimuli for the growth of vascular smooth-muscle cells after arterial injury. Deposition of platelets occurs immediately after the injury. Platelet-derived growth factor (PDGF)—a major content of the α granules in platelets—is released locally after injury to the vessel wall. PDGF stimulates smooth-muscle-cell division and migration in cell culture.11 When a polyclonal antibody to human PDGF was infused into rats subjected to balloon injury
Cell-cycle regulation
Growth inhibition with either gene therapy or a specific inhibitor of the cell cycle has been a target for basic science and clinical researchers for the past two decades. Like many specialties in medicine, basic science research has provided major impetus and innovative approaches for many clinical research studies, leading to major medical advances. The use of cell-cycle inhibitors in the treatment of restenosis is no exception. Medial vascular smooth-muscle cells are normally quiescent and
What is sirolimus?
Sirolimus is a natural macrolide immunosuppressant that was recently approved by the US Food and Drug Administration for the prophylactic treatment of renal transplant rejection. Ciclosporin A and tacrolimus are the other members of this class of compound. Ciclosporin A forms a complex with cyclophilin, whereas sirolimus and tacrolimus share a family of immunophilins known as tacrolimus binding proteins.23 The mechanism of action of this class of immunosuppressants is mainly through the binding
Cell-culture models
Growth and migration of vascular smooth-muscle cells are two major features of neointimal proliferation after vascular injury. Marx and colleagues25 were first to show that sirolimus inhibits the proliferation of vascular smooth-muscle cells through G1/S transition. The proposed mechanism of inhibition of proliferation of vascular smooth-muscle cells by sirolimus includes binding of the immunophilin tacrolimus-binding-protein 12, blockage of p70S6 kinase, impairment of pRB hyperphosphorylation,
Experimental animal models
The early findings from the cell-culture models were followed by further studies of sirolimus in restenosis with various animal models of vessel injury. Gregory and colleagues28 showed that sirolimus inhibits the development of arteriopathy in rats after femoral artery allograft transplantation and balloon injury to the carotid arteries. Using a balloon angioplasty model of porcine coronary injury, we showed that sirolimus inhibits intimal hyperplasia after balloon angioplasty of the coronary
Human studies
The potential clinical usefulness of cell-cycle inhibitors in the treatment of restenosis has generated enthusiasm among basic scientists and clinical researchers of vascular disease. However, the potential for short-term and long-term complications associated with systemic administration of immunosuppressive agents has deterred researchers from investigating the efficacy of this class of agents in the treatment of native and secondary vascular diseases. Another way to abate the robust
Conclusions
Sirolimus has been transformed from its original role as a macrolide immunosuppressive agent for combating rejection after organ transplantation to a potential treatment for restenosis after coronary stenting. The evolution often involves the translation of an important basic science discovery into a new clinical treatment. The molecular mechanisms of action of sirolimus and problems with long-term deleterious effects relating to the systemic use of sirolimus are not yet fully understood.
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