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Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury

Nature Medicine volume 9, pages 183–190 (2003)Cite this article

Abstract

Carbon monoxide (CO), one of the products of heme oxygenase action on heme, prevents arteriosclerotic lesions that occur following aorta transplantation; pre-exposure to 250 parts per million of CO for 1 hour before injury suppresses stenosis after carotid balloon injury in rats as well as in mice. The protective effect of CO is associated with a profound inhibition of graft leukocyte infiltration/activation as well as with inhibition of smooth muscle cell proliferation. The anti-proliferative effect of CO in vitro requires the activation of guanylate cyclase, the generation of cGMP, the activation of p38 mitogen-activated protein kinases and the expression of the cell cycle inhibitor p21Cip1. These findings demonstrate a protective role for CO in vascular injury and support its use as a therapeutic agent.

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Figure 1: CO suppresses intimal hyperplasia associated with chronic graft rejection.
Figure 2: CO suppresses graft infiltration by activated leukocytes.
Figure 3: CO suppresses the development of vascular lesions associated with balloon injury.
Figure 4: CO blocks SMC proliferation: role of p21Cip1 in the anti-proliferative effect of CO.
Figure 5: CO blocks SMC proliferation via generation of cGMP and activation of p38 MAPK.
Figure 6: CO activates p38 MAPK through a mechanism that requires the generation of cGMP.

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Acknowledgements

This work was supported by a grant from the Roche Organ Transplantation Research Foundation (ROTRF; 998521355) awarded to M.P.S.; an Atorvastatin Research Award (AHA) sponsored by Pfizer awarded to M.P.S.; NIH grants HL67040 (M.P.S.), HL58688 (F.H.B.), HL53458 (A.U.), HL60234 (A.M.K.C.), HL5785405 (E.T.); American Heart Association grants 9740246N (A.M.K.C.) and 0160332U (L.E.O.); an AHA sponsored by Pfizer and awarded to L.E.O.; and an Ethicon-Society of University Surgeons Resident Research Award (awarded to B.S.Z.). M.H. was partially supported by a fellowship grant awarded by the Japan Science and Technology Corporation (JST). F.H.B. is the Lewis Thomas Professor at the Harvard Medical School and is a paid consultant for Novartis Pharma.

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Author notes

  1. Leo E. Otterbein, Brian S. Zuckerbraun and Manabu Haga: L.E.O., B.S.Z. and M.H. contributed equally to this work.

Authors and Affiliations

  1. Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Montefiore University Hospital, Pittsburgh, Pennsylvania, USA

    Leo E. Otterbein, Fang Liu, Ruiping Song & Augustine M.K. Choi

  2. Department of Surgery, University of Pittsburgh School of Medicine, Montefiore University Hospital, Pittsburgh, Pennsylvania, USA

    Brian S. Zuckerbraun, Timothy R. Billiar & Edith Tzeng

  3. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Manabu Haga, Eva Csizmadia, Shivraj Tyagi, Yorihiro Akamatsu, Fritz H. Bach & Miguel P. Soares

  4. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Anny Usheva, Christina Stachulak, Natalya Bodyak & R. Neal Smith

  5. Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA

    Richard J. Flavell

  6. Instituto Gulbenkian de Ciência, Oeiras, Portugal

    Miguel P. Soares

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Corresponding authors

Correspondence to Fritz H. Bach or Augustine M.K. Choi.

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Otterbein, L., Zuckerbraun, B., Haga, M. et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med 9, 183–190 (2003). https://doi.org/10.1038/nm817

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