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J Thorac Cardiovasc Surg 2003;126:659-665
© 2003 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

Activation of mitogen-activated protein kinases during preparation of vein grafts and modulation by a synthetic inhibitor

^a The Seymour Cohn Cardiovascular Research Laboratory, Division of Cardiothoracic Surgery, Department of Surgery, New York University School of Medicine, New York, NY, USA

Preliminary results presented at the October 2001 Meeting of the American College of Surgeons.

Received for publication May 9, 2002; revisions received August 22, 2002; revisions received September 16, 2002; accepted for publication October 29, 2002.

^* Address for reprints: Aubrey C. Galloway, MD, Professor of Surgery, Director, Cardiac Surgical Research, New York University School of Medicine, 530 First Avenue, Suite 9V, New York, NY 10016, USA
galloway{at}cv.med.nyu.edu

OBJECTIVE: Long-term durability of saphenous vein grafts used for coronary artery bypass grafting is limited by neointimal formation. Arterial vascular injury is known to activate intracellular mitogen-activated protein kinases, including extracellular signal-regulated kinases and c-jun N-terminal kinases, that affect cell differentiation, proliferation, migration, and apoptosis. This study tests the hypothesis that these mitogen-activated protein kinases are activated in saphenous veins during preparation for coronary artery bypass grafting.

METHODS: Saphenous veins were harvested from 10 patients undergoing coronary artery bypass grafting. A specimen from each vein was placed in ice-cold lysis buffer immediately after harvesting (t = 0). The remaining tissue was incubated at room temperature in normal saline, 0.1% dimethylsulfoxide (vehicle), or 50 mmol/L PD98059 (mitogen-activated protein kinase kinase-1/2 inhibitor) until the vein was grafted (mean 50 minutes). To study kinetics of intracellular signaling pathways, canine saphenous veins were harvested, and mitogen-activated protein kinases and PI-3 kinase pathways were studied after different incubation time intervals. Extracted proteins were analyzed by Western blotting or in vitro kinase assay.

RESULTS: The human saphenous veins showed elevated levels of active extracellular signal-regulated kinase after harvesting (t = 0) and prior to implant (t = 1). Incubation with PD98059 resulted in decreased activation of extracellular signal-regulated kinase. Kinetics of canine saphenous veins showed extracellular signal-regulated kinase and c-jun N-terminal kinase activation, in a time-dependent manner, along with activation of the growth factor-regulated PI3 kinase pathway.

CONCLUSIONS: This study characterizes activation of extracellular signal-regulated kinases and c-jun N-terminal kinases during vein graft preparation and demonstrates the ability to inhibit extracellular signal-regulated kinase activation by simple incubation with a specific inhibitor. Further studies are needed to evaluate the significance of these findings with respect to graft durability.

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