The regulation of carbon monoxide/heme oxygenase system by hydrogen sulfide in rats with hypoxic pulmonary hypertension

目的研究新型气体信号分子硫化氢(H2S)在大鼠低氧性肺动脉高压形成中对一氧化碳(CO)/血红素加氧酶(HO-1)体系的调节作用,以深入探讨H2S在大鼠低氧性肺动脉高压形成中的病理生理意义.方法将27只大鼠随机分为4组:对照组(7只),低氧组(7只),低氧+硫氢化钠(NaHS)组(7只),低氧+炔丙基甘氨酸(PPG)组(6只).低氧21 d后分别测定肺动脉平均压、血浆H2S及CO含量,观察肺动脉平滑肌HO-1蛋白及HO-1 mRNA表达.结果随着低氧性肺动脉高压的形成,血浆H2S的含量显著下降,低氧组[(196±22)μmol/L]与对照组[(294±26)μmol/L]比较差异有显著性(P＜0.05);而CO含量、大、中、小各级肺动脉平滑肌HO-1蛋白表达[对照组、低氧组分别为(0.313±0.020)μmol/L、(0.348±0.021)μmol/L,0.66±0.08、0.79±0.08,0.64±0.05、0.77±0.08,0.54±0.05、0.76±0.09]及其mRNA表达(对照组、低氧组分别为0.573±0.148、0.813±0.052,0.532±0.131、0.831±0.043,0.473±0.102、0.819±0.032)显著升高(P均＜0.05);外源性给予H2S的供体后,低氧+NaHS组血浆H2S含量[(324±33)μmol/L]显著高于低氧组[(196±22)μmol/L,P＜0.05],肺动脉压显著下降(P＜0.05),且血浆CO含量[(0.393±0.032)μmol/L]、大、中、小各级肺动脉平滑肌HO-1蛋白表达(0.88±0.04、0.89±0.05、0.89±0.06)及mRNA表达(0.913±0.022、0.922±0.021、0.933±0.014)亦较低氧组显著升高(P均＜0.05);当给予胱硫醚γ裂解酶(CSE)抑制剂PPG后,血浆H2S的含量[(142±45)μmol/L]显著降低(P＜0.05),肺动脉压亦较低氧组显著升高(P＜0.05),而血浆CO含量[(0.274±0.032)μmol/L]、大、中、小各级肺动脉平滑肌细胞HO-1蛋白表达(0.54±0.06、0.56±0.04、0.39±0.06)及mRNA表达(0.423±0.043、0.418±0.091、0.382±0.051)亦较低氧组显著降低(P均＜0.05).结论 H2S在低氧性肺动脉高压形成中对CO/HO-1体系具有重要的调节作用,H2S可通过CO/HO-1体系参与低氧时肺循环的调节.To explore the impact of hydrogen sulfide (H2S) on the carbon monoxide (CO)/heme oxygenase-1 (HO-1) system in pulmonary artery of hypoxic rats.Twenty-seven rats were randomly divided into four groups: hypoxic group (n = 7), hypoxic + NaHS group (n = 7), hypoxic + propargylglycine (PPG) group (n = 6) and control group (n = 7). After 21 days, pulmonary artery mean pressure (mPAP) of each rat was evaluated and the plasma concentration of H2S and CO were measured. The expression of HO-1 in pulmonary arteries of each rat was detected by immunohistochemistry technique. In situ hybridization for HO-1 mRNA in pulmonary arteries was also observed.mPAP was significantly increased in hypoxic rats [(20.5 +/- 2.9) mm Hg] as compared with that of normal controls [(14.8 +/- 3.6) mm Hg, P <0.05]. The plasma H2S[(196+/-22 ) micromol/L] of hypoxic group was decreased significantly compared with control group [(294+/-26) micromol/L, P < 0. 05]. The plasma CO and the expression of HO-1 protein and mRNA in large, medium and small sized pulmonary arteries of hypoxic group [ (0.348 +/- 0.021) micromol/L, 0.79+/-0.08, 0.77+/-0.08, 0.76+/-0.09, 0.813+/-0.052, 0.831+/-0.043, 0.819+/-0.032, respectively] were significantly increased compared to control rats [(0.313+/-0. 020) micromol/L, 0.66+/-0.08, 0.64+/-0.05, 0.54+/-0.05; 0.573 +/- 0.148, 0.532+/-0.131, 0.473+/-0.102, respectively; all P <0.05]. Compared with hypoxic group, the plasma H2S of hypoxic + NaHS group [(324+/-33 ) micromol/L] was significantly increased, and mPAP was decreased significantly (all P < 0.05). Meanwhile, compared with hypoxic group, the plasma concentration of CO [(0.393+/-0.032) micromol/L], the expression of HO-1 protein and mRNA in large, medium and small sized pulmonary arteries were significantly increased in hypoxic + NaHS group (0.88+/-0.04, 0.89 +/- 0.05, 0.89 +/- 0.06; 0.913 +/- 0.022, 0.922 +/- 0.021, 0.933 +/- 0.014, respectively; all P < 0.05). However, compared with hypoxic group, the plasma concentration of H2S was decreased significantly in hypoxic + PPG group [(142 +/- 45) micromol/L, P < 0. 05], and mPAP was increased significantly (P < 0.05). With the decrease of H2S in hypoxic + PPG group, the plasma concentration of CO, the expression of HO-1 protein and mRNA in large, medium and small sized pulmonary arteries were significantly decreased [(0.274 +/- 0.032) micromol/L; 0.54 +/- 0.06, 0.56+/-0.04, 0.39+/-0.06; 0.423 +/- 0.043, 0.418 +/- 0.091, 0.382+/-0.051 respectively; all P <0.05] compared to hypoxic group.H2S upregulated CO/HO-1 system in pulmonary arteries of hypoxic rats.国家自然科学基金; 国家重点基础研究发展计划(973计划); 高等学校博士学科点专项科研项目PubMed中文核心期刊要目总览(PKU)中国科学引文数据库(CSCD)010659-6632