内皮源性硫化氢在雌激素抗动脉粥样硬化中的作用及机制

Role and mechanism of endothelial hydrogen sulfide in anti-atherosclerosis effect of estrogen

目的:探讨内皮源性硫化氢(H2S)在雌激素诱导的抗动脉粥样硬化过程中的作用及其机制。方法:在体外培养的人脐静脉内皮细胞(HUVECs)上观察17β-雌二醇(E2)促进H2S快速释放的效应,并进一步观察雌激素受体在此过程中的作用。在去势雌性ApoE–/–C57BL/6小鼠中建立动脉粥样硬化模型,实验分为去势组(OVX)、去势+E2治疗组(OVX+E2)、去势+E2+内源性H2S生成酶抑制剂DL-炔丙基甘氨酸(PPG)治疗组(OVX+E2+PPG),观察各组大鼠血液中H2S的浓度和动脉粥样斑块大小。结果:E2可以促进HUVECs快速释放H2S,且具有时间效应和浓度效应。雌激素受体α亚型激动剂丙基吡唑三醇(而不是β亚型激动剂二芳丙腈)可以模拟E2促H2S释放效应,雌激素受体拮抗剂ICI 182780可以阻断E2促H2S释放效应。在动物模型上,与OVX相比,OVX+E2组动脉粥样硬化明显改善,血液中H2S浓度升高;而OVX+E2+PPG组动脉粥样硬化无明显改善,H2S浓度无明显差异。结论:雌激素通过细胞膜上的ERα促进内皮源性H2S的快速释放,H2S在雌激素抗动脉粥样硬化的过程中起着重要作用。

AIM： To investigate possible role and mechanism of endothelial hydrogen sulfide （H2 S） in the an- ti-atherosclerosis effect of estrogen. METHODS ： For in vitro experiment, cultured human umbilical vein endothelial cells （HUVECs） were treated with 1713-estradiol （E2）, estrogen receptor α （ERα） agonist propylpyrazole triol （PPT）, estro- gen receptor 13 （ER13） agonist diarylpropionitrile （DPN） and estrogen receptor antagonist ICI 182780 （ICI） for 5 min, and then the concentration of H2 S in cell culture supernatants was detected by sensitive sulphur electrode assay. For in vivo ex- periment, high-fat diet-fed and ovariectomized （OVX） female ApoE ~ / - C57BL/6 mice were randomly divided into 3 groups and treated with placebo （OVX group）, E2 （OVX ＋ E2 group） and E2 plus cystathionine ~/-lyase （CSE） inhibitor DL-prop- argylglycine （PPG） （OVX ＋ E2 ＋ PPG group）, respectively, and the blood concentration of I-I2S and the atherosclerotic plaque size were detected 8 weeks later. RESULTS： E2 significantly enhanced the release of H2S from HUVECs in a con- centration-and time-dependant manner which could be blocked by the administration of ICI. Meanwhile, ERa agonist PPT, not ER13 agonist DPN, demonstrated similar effects to E2. Compared with OVX group, the atherosclerosis in mice was attenuated and the blood concentration of H2S was elevated in OVX ＋ E2 group, while no significant changes were detected in OVX ＋ E2 ＋ PPG group. CONCLUSION： Endothelial H2S can be rapidly released when membrane ERa is activated by estrogen, which plays a very important role in the anti-atherosclerosis effect of estrogen. [