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Ann Thorac Surg 2001;71:1865
© 2001 The Society of Thoracic Surgeons
a Department of Anatomic Pathology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA
e-mail: ratlifn{at}cesmtp.ccf.org
It has become clear over time, primarily because of the pioneering work of the late Russell Ross and colleagues, that the response to injury, any kind of injury, of the arterial and even venous intima is relatively monomorphic, consisting of the migration of smooth muscle cells into the intima, the proliferation of smooth muscle cells in the intima, and the synthesis and secretion by those same smooth muscle cells of matrix proteins and collagen. This entire process—migration, proliferation, and synthesis—results in intimal thickening, which, by itself, can significantly stenose a vein graft and is also the first step in the development of vein graft atherosclerosis. A similar reaction is the fundamental mechanism of restenosis after angioplasty, and reversing or preventing it is of major importance in the treatment of ischemic heart disease.
Along with angiotensin II, endothelin, and platelet-derived growth factor, serotonin (5-hydroxytryptamine) is a mediator of vascular smooth muscle cell proliferation. Sharma and associates identified a commercially available selective antagonist of the serotonin receptor in vascular smooth muscle cells. The antagonist has a complex chemical nomenclature (noted in their report) but is commonly called sarpogrelate. They investigated whether inhibition of the serotonin receptor could prevent the serotonin-induced proliferation of smooth muscle cells isolated from porcine coronary arteries. The authors verified inhibition of serotonin-induced proliferation of smooth muscle cells but found no inhibition of smooth muscle cell proliferation induced by platelet-derived growth factor, endothelin, or angiotensin II.
Sharma and colleagues investigated mechanisms by which this inhibition took place and found that serotonin promoted activation of mitogen-activated protein (MAP) kinase, the induction of protooncogenes c-fos and c-jun, and increased levels of intracellular free calcium as part of the induction of cell proliferation. Using a sophisticated study, the authors demonstrated that sarpogrelate blocked each of those signal transduction pathways; it suppressed the activation of MAP kinase, the expression of c-fos and c-jun protooncogenes, and the increase in intracellular calcium concentration induced by serotonin.
As they noted, these data support the concept that blocking serotonin receptors may aid in the prevention of both restenosis after angioplasty and vein graft stenosis. The studies by Sharma and coauthors were done in vitro using cultured smooth muscle cells. We should all eagerly await the outcome of follow-up studies in live animals.
Currently, prevention of restenosis is being attempted by drugs that block coagulation. The use of intravascular irradiation to prevent restenosis is in its infancy. The possibility of a drug that specifically inhibits one pathway of the activation of proliferation in vascular smooth muscle cells is very exciting.
Related Article
Ann. Thorac. Surg. 2001 71: 1856-1864.
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