Effects of sulfur dioxide on hypoxic pulmonary vascular structural remodeling.
Hypoxic pulmonary hypertension is a pathophysiological process important in the development of various cardiopulmonary diseases. Recently, we found that sulfur dioxide could be produced endogenously by pulmonary vessels, and that it showed vascular regulatory capabilities. In this paper, we examined the role of sulfur dioxide in hypoxic pulmonary vascular structural remodeling (HPVSR). A total of 48 Wistar rats were divided into six groups. Rats in the hypoxic group, hypoxic+sulfur dioxide group, and hypoxic+hydroxamate group were left under hypoxic conditions, whereas the control group, control+sulfur dioxide group, and control+hydroxamate group rats were left in room air. For each group, we measured the pulmonary arterial pressure, sulfur dioxide content in plasma and lung tissue, glutamate oxaloacetate transaminase 1 and 2 mRNAs, micro- and ultra-structural changes in pulmonary arteries, proliferation of pulmonary smooth muscle cells, vascular collagen metabolism, pulmonary endothelial cell inflammatory response, and pulmonary vascular endothelin-1 production in the rats. In hypoxic rats, the content of sulfur dioxide in plasma and lung tissue decreased significantly in comparison with those in the control groups, and significant pulmonary hypertension, pulmonary vascular structural remodeling, and increased vascular inflammatory response were also observed in hypoxic rats. Sulfur dioxide donor significantly downregulated Raf-1, mitogen-activated protein kinase kinase-1 (MEK-1) and p-ERK/ERK, and inhibited pulmonary vascular smooth muscle cell proliferation, collagen remodeling and pulmonary vascular endothelial cell nuclear factor-kappaB (NF-kappaB), and intercellular adhesion molecule 1 (ICAM-1) expressions. It also prevented pulmonary hypertension and pulmonary vascular structural remodeling in association with the upregulated sulfur dioxide/glutamate oxaloacetate transaminase pathway. Hydroxamate, however, advanced pulmonary hypertension, pulmonary vascular structural remodeling, and inflammatory response of the pulmonary artery in association with a downregulated sulfur dioxide/glutamate oxaloacetate transaminase pathway. The results suggested that sulfur dioxide markedly inhibited Raf-1, MEK-1, and the phosphorylation of extracellular signal-regulated kinase (ERK), and then inhibited pulmonary arterial smooth muscle cell (PASMC) proliferation induced by hypoxia. The downregulated sulfur dioxide/glutamate oxaloacetate transaminase pathway may be involved in the mechanisms responsible for pulmonary hypertension and pulmonary vascular structural remodeling.
Sun
Yan
Y
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Tian
Yue
Y
Prabha
Mainali
M
Liu
Die
D
Chen
Stella
S
Zhang
Rongyuan
R
Liu
Xueqin
X
Tang
Chaoshu
C
Tang
Xiuying
X
Jin
Hongfang
H
Du
Junbao
J
D000818:Animals; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000235:genetics / Q000378:metabolism; D024442:Aspartate Aminotransferase, Mitochondrial / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure; D049109:Cell Proliferation; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D019908:Proto-Oncogene Proteins c-raf; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013458:Sulfur Dioxide / Q000097:blood / Q000378:metabolism*
D012333:RNA, Messenger; D013458:Sulfur Dioxide; D024443:Aspartate Aminotransferase, Cytoplasmic; D024442:Aspartate Aminotransferase, Mitochondrial; D019908:Proto-Oncogene Proteins c-raf; C546782:Raf1 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D048369:MAP Kinase Kinase 1