Hydrogen sulfide induces apoptosis of pulmonary artery smooth muscle cell in rats with pulmonary hypertension induced by high pulmonary blood flow.
BACKGROUND
Abnormal apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important pathophysiological process in the pulmonary artery structural remodeling and pulmonary hypertension. We investigated possible effect of endogenous hydrogen sulfide (H2S) on apoptosis of PASMCs during the development of pulmonary hypertension induced by high pulmonary blood flow.


METHODS
Thirty-nine male Sprague-Dawley rats were randomly assigned to 4-week control, 4-week shunt, 4-week shunt + propargylglycine (PPG), 11-week control, 11-week shunt and 11-week shunt + sodium hydrosulfide (NaHS) groups. Rats in 4-week shunt, 4-week shunt + PPG, 11-week shunt and 11-week shunt + NaHS groups underwent an abdominal aorta-inferior vena cava shunt. Rats in 4-week shunt + PPG group were intraperitoneally injected with PPG, an inhibitor of endogenous H2S production, for 4 weeks. Rats in 11-week shunt + NaHS group were intraperitoneally injected with NaHS, a H2S donor, for 11 weeks. Lung tissue H2S was evaluated by sulfide-sensitive electrode. Apoptosis of PASMCs were detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). Expressions of Fas, bcl-2 and caspase-3 in the PASMCs were analyzed with immunochemical staining.


RESULTS
Four weeks after the shunting operation, the apoptosis of PASMCs and expression of Fas and caspase-3 were significantly decreased (P < 0.01), but expression of bcl-2 increased significantly (P < 0.01). PPG administration further inhibited the apoptosis of PASMCs, downregulated the expression of Fas and caspase-3 (P < 0.01), but increased the expression of bcl-2 (P < 0.01). After 11 weeks of shunting operation, the apoptosis of PASMCs and expression of Fas and caspase-3 were significantly decreased (P < 0.01), but expression of bcl-2 increased obviously (P < 0.01). NaHS administration significantly increased the apoptosis of PASMCs, upregulated the expression of Fas and caspase-3, but inhibited the expression of bcl-2.


CONCLUSIONS
H2S induces the apoptosis of PASMCs in the development of high pulmonary blood flow-induced pulmonary hypertension by activating the Fas pathway and inhibiting the bcl-2 pathway.
Li
Wei
W
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Jin
Hong-Fang
HF
Liu
Die
D
Sun
Jing-Hui
JH
Jian
Pei-Jun
PJ
Li
Xiao-Hui
XH
Tang
Chao-Shu
CS
DU
Jun-Bao
JB
D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001783:Blood Flow Velocity / Q000502:physiology; D015153:Blotting, Western; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000503:physiopathology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects*; D011651:Pulmonary Artery / Q000166:cytology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000480:Alkynes; C009055:propargylglycine; D005998:Glycine; D006862:Hydrogen Sulfide