Carbon monoxide reverses established pulmonary hypertension.
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.
Zuckerbraun
Brian S
BS
Department of Surgery Transplant Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Chin
Beek Yoke
BY
Wegiel
Barbara
B
Billiar
Timothy R
TR
Czsimadia
Eva
E
Rao
Jayashree
J
Shimoda
Larissa
L
Ifedigbo
Emeka
E
Kanno
Shin
S
Otterbein
Leo E
LE
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002248:Carbon Monoxide / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000628:therapy*; D000860:Hypoxia; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011651:Pulmonary Artery / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley
D009569:Nitric Oxide; D002248:Carbon Monoxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse