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J Thorac Cardiovasc Surg 2005;130:1573-1580
© 2005 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

The induction of heme oxygenase 1 decreases contractility in human internal thoracic artery and radial artery grafts

Paul Achouh, MD a , * , Serge Simonet, PhD b , Cécile Badier-Commander, PhD b , Catherine Chardigny, MD, PhD a , Christine Vayssettes-Courchay, PhD b , Rachid Zegdi, MD, PhD a , Ziad Khabbaz, MD a , Jean-Noël Fabiani, MD, PhD a , Tony J. Verbeuren, PhD b

a Department of Cardiovascular Surgery, European Hospital Georges Pompidou, Paris, France, and the Department of Angiology,
b Servier Research Institute, Suresnes, France

* Address for reprints: Paul Achouh, MD, Department of Cardiothoracic and Vascular Surgery, University of Texas-Houston Medical School, Memorial Hermann Hospital. 6410 Fannin Street, Suite 450, Houston, TX 77030 (Email: paulachouh{at}softhome.net).

OBJECTIVE: Spasm remains a potential problem encountered during the use of arterial grafts in coronary artery bypass surgery. Heme oxygenase plays a role in the control of arterial vasoreactivity. Heme oxygenase exists in 2 constitutive isoforms (heme oxygenase 2 and 3) and an inducible isoform (heme oxygenase 1). The aim of our study was to induce heme oxygenase 1 by using hemin in human internal thoracic and radial arteries and to evaluate the effect of this induction on the contractility of these arterial grafts.

METHODS: Segments of human arterial grafts obtained from patients undergoing isolated coronary artery bypass surgery were incubated in organ chambers for 4 hours in the presence of 10–4 mol/L hemin. Concentration-response curves to norepinephrine were obtained in control and hemin-treated arterial rings. Heme oxygenase 1 expression was evaluated by using enzyme-linked immunosorbent assays and immunohistochemical staining.

RESULTS: The contractility of the arterial rings to norepinephrine was significantly reduced after incubation with hemin. Zinc protoporphyrin (an inhibitor of heme oxygenase) reversed the effect of hemin, whereas the inhibitor of nitric oxide synthase had no effect. The inhibitor of soluble guanylate cyclase blocked the decrease in contractility induced by hemin. Immunohistochemical staining revealed a large expression of heme oxygenase 1 in all vascular layers of hemin-treated internal thoracic artery and radial artery rings. Enzyme-linked immunosorbent assay studies showed a significant increase in heme oxygenase 1 levels in hemin-treated internal thoracic artery and radial artery rings.

CONCLUSION: Hemin caused in vitro induction of heme oxygenase 1 in human internal thoracic artery and radial artery grafts. This induction resulted in a reduced contractility to norepinephrine, partially through the cyclic guanosine monophosphate–dependent pathway. This effect was independent from nitric oxide synthesis.

Abbreviations and Acronyms ELISA = enzyme-linked immunosorbent assay; GMP = guanosine monophosphate; HO = heme oxygenase; ITA = internal thoracic artery; LNA = Nw-nitro-L-arginine; NE = norepinephrine; NO = nitric oxide; ODQ = 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one; RA = radial artery; ZnPP = zinc protoporphyrin






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