Sulfur Dioxide Inhibits Extracellular Signal-regulated Kinase Signaling to Attenuate Vascular Smooth Muscle Cell Proliferation in Angiotensin II-induced Hypertensive Mice.
BACKGROUND
Clarifying the mechanisms underlying vascular smooth muscle cell (VSMC) proliferation is important for the prevention and treatment of vascular remodeling and the reverse of hyperplastic lesions. Previous research has shown that the gaseous signaling molecule sulfur dioxide (SO2) inhibits VSMC proliferation, but the mechanism for the inhibition of the angiotensin II (AngII)-induced VSMC proliferation by SO2has not been fully elucidated. This study was designed to investigate if SO2inhibited VSMC proliferation in mice with hypertension induced by AngII.


METHODS
Thirty-six male C57 mice were randomly divided into control, AngII, and AngII + SO2groups. Mice in AngII group and AngII + SO2group received a capsule-type AngII pump implanted under the skin of the back at a slow-release dose of 1000 ng·kg-1·min-1. In addition, mice in AngII + SO2received intraperitoneal injections of SO2donor. Arterial blood pressure of tail artery was determined. The thickness of the aorta was measured by elastic fiber staining, and proliferating cell nuclear antigen (PCNA) and phosphorylated-extracellular signal-regulated kinase (P-ERK) were detected in aortic tissues. The concentration of SO2 in serum and aortic tissue homogenate supernatant was measured using high-performance liquid chromatography with fluorescence determination. In the in vitro study, VSMC of A7R5 cell lines was divided into six groups: control, AngII, AngII + SO2, PD98059 (an inhibitor of ERK phosphorylation), AngII + PD98059, and AngII + SO2 + PD98059. Expression of PCNA, ERK, and P-ERK was determined by Western blotting.


RESULTS
In animal experiment, compared with the control group, AngII markedly increased blood pressure (P < 0.01) and thickened the aortic wall in mice (P < 0.05) with an increase in the expression of PCNA (P < 0.05). SO2, however, reduced the systemic hypertension and the wall thickness induced by AngII (P < 0.05). It inhibited the increased expression of PCNA and P-ERK induced by AngII (P < 0.05). In cell experiment, PD98059, an ERK phosphorylation inhibitor, blocked the inhibitory effect of SO2on VSMC proliferation (P < 0.05).


CONCLUSIONS
ERK signaling is involved in the mechanisms by which SO2inhibits VSMC proliferation in AngII-induced hypertensive mice via ERK signaling.
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Hui-Juan
HJ
Wu
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Ya-Qian
YQ
Huang
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Qing-Hua
QH
Chen
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Xiao-Yu
XY
Tian
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Jia
J
Liu
Department of Physiology and Pathophysiology, Peking University Health Science Centre; Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing 100091, China.
Chao-Shu
CS
Tang
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Hong-Fang
HF
Jin
Department of Pediatrics, Peking University First Hospital, Beijing 100034; Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing 100091, China.
Jun-Bao
JB
Du
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013458:Sulfur Dioxide / Q000627:therapeutic use*
D013458:Sulfur Dioxide; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases