Abstract
BackgroundHigh prevalence of obstructive sleep apnea (OSA) in the pulmonary hypertension (PH) population suggests that chronic intermittent hypoxia (CIH) is an important pathogenic factor of PH. However, the exact mechanism of CIH induced PH is not clear. One of the molecules that plays a key role in regulating pulmonary artery function under hypoxic conditions is superoxide dismutase 2 (SOD2).MethodsOur study utilized heterozygous SOD2−/+ mice firstly in CIH model to explore the exact role of SOD2 in CIH causing PH. Expression of SOD2 was analyzed in CIH model. Echocardiography and pulmonary hypertension were measured in wild type (WT) and SOD2−/+ mice under normal air or CIH condition. Hematoxylin–Eosin (H&E) staining and masson staining were carried out to evaluate pulmonary vascular muscularization and remodeling. Micro-PET scanning of in vivo 99mTc-labelled- MAG3-anti-CD11b was applied to assess CD11b in quantification and localization. Level of nod-like receptor pyrin domain containing 3 (NLRP3) was analyzed by real time PCR and immunohistochemistry (IHC).ResultsResults showed that SOD2 was down-regulated in OSA/CIH model. Deficiency of SOD2 aggravated CIH induced pulmonary hypertension and pulmonary vascular hypertrophy. CD11b+ cells, especially monocytic myeloid cell line-Ly6C+Ly6G− cells, were increased in the lung, bone marrow and the blood under CIH condition, and down-regulated SOD2 activated NLRP3 in CD11b+ cells. SOD2-deficient-CD11b+ myeloid cells promoted the apoptosis resistance and over-proliferation of human pulmonary artery smooth muscle cells (PASMCs) via up-regulating NLRP3.ConclusionCIH induced down-regulating of SOD2 increased pulmonary hypertension and vascular muscularization. It could be one of the mechanism of CIH leading to PH.
Highlights
Obstructive sleep apnea (OSA) is a public health problem in 5–10% people, which causes episodic hypoxemia and elevates blood pressure and markers of oxidative stress, inflammation, and hypercoagulation [1,2,3]
superoxide dismutase 2 (SOD2) was down-regulated in obstructive sleep apnea (OSA)/chronic intermittent hypoxia (CIH) model We analyzed the expression of SOD2 of 117 participants in the blood to compare the deficiency of SOD2 in OSA groups and the control group
Male participants are more than the female in the group of OSA compared to the control group, while no difference in the age (Table 1)
Summary
Obstructive sleep apnea (OSA) is a public health problem in 5–10% people, which causes episodic hypoxemia and elevates blood pressure and markers of oxidative stress, inflammation, and hypercoagulation [1,2,3]. Several studies have reported OSA as a risk factor for systemic hypertension and various cardiovascular diseases [4, 5]. Pulmonary hypertension (PH) was the most common cause of death in cardiovascular complications. High prevalence of obstructive sleep apnea (OSA) in the pulmonary hypertension (PH) population suggests that chronic intermittent hypoxia (CIH) is an important pathogenic factor of PH. One of the molecules that plays a key role in regulating pulmonary artery function under hypoxic conditions is superoxide dismutase 2 (SOD2). Methods: Our study utilized heterozygous SOD2−/+ mice firstly in CIH model to explore the exact role of SOD2 in CIH causing PH. Expression of SOD2 was analyzed in CIH model. Echocardiography and pulmonary hypertension were measured in wild type (WT) and SOD2−/+ mice under normal air or CIH condition. Level of nod-like receptor pyrin domain containing 3 (NLRP3) was analyzed by real time PCR and immunohistochemistry (IHC)
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