Published online 14 August 2006 doi:10.1084/jem.20052267
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 9, 2109-2119
Carbon monoxide reverses established pulmonary hypertension
Brian S. Zuckerbraun3,
Beek Yoke Chin1,
Barbara Wegiel1,
Timothy R. Billiar3,
Eva Czsimadia1,
Jayashree Rao3,
Larissa Shimoda2,
Emeka Ifedigbo4,
Shin Kanno3, and
Leo E. Otterbein1
1 Department of Surgery Transplant Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
2 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224
3 Department of Surgery and 4 Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213
CORRESPONDENCE Leo E. Otterbein: lotterbe{at}bidmc.harvard.edu
Pulmonary arterial hypertension (PAH) is an incurable disease characterized by a progressive increase in pulmonary vascular resistance leading to right heart failure. Carbon monoxide (CO) has emerged as a potently protective, homeostatic molecule that prevents the development of vascular disorders when administered prophylactically. The data presented in this paper demonstrate that CO can also act as a therapeutic (i.e., where exposure to CO is initiated after pathology is established). In three rodent models of PAH, a 1 hour/day exposure to CO reverses established PAH and right ventricular hypertrophy, restoring right ventricular and pulmonary arterial pressures, as well as the pulmonary vascular architecture, to near normal. The ability of CO to reverse PAH requires functional endothelial nitric oxide synthase (eNOS/NOS3) and NO generation, as indicated by the inability of CO to reverse chronic hypoxia-induced PAH in eNOS-deficient (nos3–/–) mice versus wild-type mice. The restorative function of CO was associated with a simultaneous increase in apoptosis and decrease in cellular proliferation of vascular smooth muscle cells, which was regulated in part by the endothelial cells in the hypertrophied vessels. In conclusion, these data demonstrate that CO reverses established PAH dependent on NO generation supporting the use of CO clinically to treat pulmonary hypertension.
Abbreviations used: eNOS, endothelial NOS; FHH, fawn-hooded hypertensive; HO-1, heme oxygenase–1; HPF, high power field; HRP, horseradish peroxidase; iNOS, inducible NOS; IVS, intraventricular septum; MCT, monocrotaline sodium; mPAP, mean pulmonary arterial pressure; mRVP, mean right ventricular pressure; NO, nitric oxide; NOS, NO synthase; PAEC, pulmonary artery endothelial cell; PAH, pulmonary arterial hypertension; PAVSM, pulmonary artery vascular smooth muscle; PI, propidium iodide; RV and LV, right and left ventricle, respectively; RVH, right ventricular hypertrophy; TUNEL, Tdt-mediated dUTP-biotin nick-end labeling.
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