Carbon monoxide reverses established pulmonary hypertension

Abstract

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.

CO metabolism, sensing, and signaling

“…Therefore, in contrast to other studies showing the antiapoptotic effects of CO, Fas/CD95-induced cell death in Jurkat T cells is augmented by exposure to CO partially occurring via inhibition in the activation of the extracellular signal-regulated kinase (ERK) MAPK [154]. Furthermore, CO has been demonstrated to reverse established pulmonary arterial hypertension in vivo, an incurable disease characterized by a progressive increase in pulmonary vascular resistance, leading to heart failure [134]. This occurs in part suppressing growth and increasing apoptosis of the smooth muscle cells of the pulmonary artery.…”

“…The ability of CO to exert its remodeling effects requires the expression and function of eNOS/NOS3. Indeed, NO acts in part as the effector molecule to induce cell death of pulmonary artery smooth muscle cells while preserving the endothelial cells [134] (Fig. 2).…”

“…Additional candidates that function as downstream target molecules of CO signaling include the tumor suppressor protein caveolin-1 (cav-1), the anti-inflammatory nuclear regulator early growth response transcription factor-1 (Egr-1), the hypoxia-inducible factor 1 (HIF1a), the 70-kD heat shock protein (Hsp70), the interferon regulatory factor (IRF), the nuclear factor j-light-chain-enhancer of activated B cells (NFjB), the NOS/NO system, the phosphatidylinositol-3-kinase (PI3K)-Akt, PPAR-c, and the signal transducers and activators of transcription (STAT) [20,21,42,[127][128][129][130][131][132][133][134][135][136][137] (Fig. 1).…”

Heme Oxygenase-1/Carbon Monoxide

“…Low concentration CO can reverse established pulmonary hypertension in rats, induced by chronic hypoxia or monocrotaline administration (109). Observations of COmediated tissue protection have also been described in transplantation of heart, lung, kidney, liver, and intestinal allografts or xenografts, whereby application of CO to the recipient or to the graft reduced inflammation and apoptosis associated with I/ R injury, thus reducing the probability of graft rejection (12,(110)(111)(112)(113)(114).…”

Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase–Dependent Nitric Oxide Generation

“…Primary rat and mouse pulmonary artery smooth muscle cells (PASMCs) were isolated as previously described 41 and cultured in DMEM (low glucose):F12 medium (1:1 vol/vol) with 10% FBS, 2 mmol/L L-glutamine, 100 U/mL penicillin, and 100 g/mL streptomycin in a 37°C, 5% CO 2 incubator. PASMCs from passages 3 through 7 only were used.…”