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

Abstract

Background-Pulmonary arterial hypertension is a progressive proliferative vasculopathy of the small pulmonary arteries that is characterized by a primary failure of the endothelial nitric oxide and prostacyclin vasodilator pathways, coupled with dysregulated cellular proliferation. We have recently discovered that the endogenous anion salt nitrite is converted to nitric oxide in the setting of physiological and pathological hypoxia. Considering the fact that nitric oxide exhibits vasoprotective properties, we examined the effects of nitrite on experimental pulmonary arterial hypertension. Methods and Results-We exposed mice and rats with hypoxia or monocrotaline-induced pulmonary arterial hypertension to low doses of nebulized nitrite (1.5 mg/min) 1 or 3 times a week. This dose minimally increased plasma and lung nitrite levels yet completely prevented or reversed pulmonary arterial hypertension and pathological right ventricular hypertrophy and failure. In vitro and in vivo studies revealed that nitrite in the lung was metabolized directly to nitric oxide in a process significantly enhanced under hypoxia and found to be dependent on the enzymatic action of xanthine oxidoreductase. Additionally, physiological levels of nitrite inhibited hypoxia-induced proliferation of cultured pulmonary artery smooth muscle cells via the nitric oxide-dependent induction of the cyclin-dependent kinase inhibitor p21 Waf1/Cip1 . The therapeutic effect of nitrite on hypoxia-induced pulmonary hypertension was significantly reduced in the p21-knockout mouse; however, nitrite still reduced pressures and right ventricular pathological remodeling, indicating the existence of p21-independent effects as well. Conclusion-These studies reveal a potent effect of inhaled nitrite that limits pathological pulmonary arterial hypertrophy and cellular proliferation in the setting of experimental pulmonary arterial hypertension. (Circulation. 2010;121:98-109.)

Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction

“…has shown efficacy in reducing pulmonary pressures and preventing right ventricular hypertrophy (19)(20)(21). More recent work has demonstrated that acute IV administration of nitrite improves exercise capacity in patients with HFpEF, a group at high risk for secondary (Group 2) PH (22).…”

H2S inhibition of chemical hypoxia-induced proliferation of HPASMCs is mediated by the upregulation of COX-2/PGI2

“…indicates that ROS play a critical role in hypoxia-induced cell proliferation (3,9). In this study, to examine the role of ROS in the proliferation of HPASMCs, the cells were exposed to the exogenous ROS donor, H 2 O 2 .…”

“…Reportedly, in human pulmonary artery smooth muscle cells (HPASMCs), NADPH oxidase (NOX)4 mediates cell proliferation triggered by transforming growth factor-β1 (TGF-β1) (3). The inhibition of oxidative stress with nitrite or superoxide dismutase (SOD) has been shown to ameliorate PAH (8,9). Of note, prostacyclin (also known as prostaglandin I2 or PGI 2 ), an effective but expensive clinical drug, has been used for the treatment of PAH via vasodilatation (10).…”

Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats

“…Studies have identified multiple enzymes that possess nitrite reductase activity, including XOR. This potential nitrite reductase has been suggested to be one of the predominant reductases within the vasculature (43). Based upon this knowledge, the role of XOR in mediating the effects of sodium nitrite was investigated.…”