SUMMARY Since the 1980 s nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), the endogenous gas molecules produced from metabolic pathway, have been realized as signal molecules to be involved in the r...SUMMARY Since the 1980 s nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), the endogenous gas molecules produced from metabolic pathway, have been realized as signal molecules to be involved in the regulation of body homeostasis and to play important roles under physiological and pathophysiological conditions. The researches on these endogenous gas signal molecules opened a new avenue in life science. To explore the new member of gasotransmitter family, other endogenous gas molecules which have been regarded as metabolic waste up to date, and their biological regulatory effects have been paid close attention to in the current fields of life science and medicine. Sulfur dioxide (SO2) can be produced endogenously from normal metabolism of sulfur-containing amino acids. L-cysteine is oxidized via cysteine dioxygenase to L-cysteinesulfinate, and the latter can proceed through transamination by glutamate oxaloacetate transaminase (GOT) to β-sulfinylpyruvate which decomposes spontaneously to pyruvate and SO2. In mammals, activated neutrophils by oxidative stress can convert H2S to sulfite through a reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase-dependent process. The authors detected endogenous production of SO2 in all cardiovascular tissues, including in heart, aorta, pulmonary artery, mesenteric artery, renal artery, tail artery and the plasma SO2 content. As the key enzyme producing SO2, GOT mRNA in cardiovascular system was detected and found to be located enrichedly in endothelial cells and vascular smooth muscle cells near the endothelial layer.When the normal rats were treated with hydroxamate(HDX), a GOT inhibitor, at a dose of 3.7 mg/kg body weight, the blood pressure (BP) went high markedly, the ratio of wall thickness to lumen radius was increased by 18.34%, and smooth muscle cell proliferation was enhanced. The plasma SO2 level in the rats injected with 125 μmol/kg body weight SO2 donor was increased to 721.98±30.11 μmol/L at the end of 30 seconds, while the blood pressure was decreased to the lowest point 65.0± 4.9 mm Hg at the end of 1 minute. The above results showed that endogenous SO2 might be involved in the maintenance of blood pressure and normal vascular structure. In spontaneous hypertensive rat (SHR) animal model, exogenous supplement of SO2 donor decreased the BP, the media cross-sectional area, and pressure of the media and the ratio of wall thickness to lumen radius in the SHR. Moreover, the proliferative index of aortic smooth muscle cells was decreased in the SHR treated with SO2 donor compared with that in SHR. The above data showed that SO2 could prevent the aortic structural remodeling by inhibiting the proliferation of aortic smooth muscle cells.The authors observed the direct vasorelaxant effects of SO2 on the aortic ring pre-treated with norepinephrin (NE). SO2 donor at a concentration of 25—100 μmol/L relaxed the aortic ring temporarily and slightly, but SO2 donor at a concentration of 1—12 mmol/L induced relaxation of the ring in a concentration-dependent manner. Administration with nicardipine, an L-type calcium channel blocker other than glibenclamide, an ATP sensitive potassium channel (KATP channel) blocker or removal of vascular endothelium could decrease the SO2-induced vasorelaxation. In hypoxic pulmonary hypertension animal model, SO2 donor decreased the mean pulmonary artery pressure and the systolic pulmonary artery pressure (P<0.01), respectively as compared with hypoxic group, and alleviated obviously the hypoxic pulmonary vascular structural remodeling. The percentage of muscularized arteries of small pulmonary vessels was significantly decreased in hypoxia+SO2 donor-treated rats compared with that of hypoxic rats (P<0.01), while the percentage of non-muscularized vessels was obviously higher in hypoxia with SO2 donor-treated rats than that of hypoxic rats (P<0.01). Similarly, SO2 obviously decreased relative media area and relative media thickness of small muscularized pulmonary arteries in hypoxic rats (P<0.01). The above data showed that SO2 might play an important role in development of hypoxic pulmonary hypertension.Perfusion with SO2 donor (10-6—10-3 mol/L) to the isolated rat heart obviously inhibited the left ventricular peak rate of contraction ( + LV dp/ dtmax) , peak rate of relaxation ( -LV dp/ dtmax) and difference of left ventricular pressure ( ΔLVP) in a concentration dependent manner. Nicardipine, an L-type calcium channel blocker, could partly antagonize the inhibitory effect of SO2 on the heart function. In a word, SO2 could be endogenously generated in cardiovascular tissues and exert important cardiovascular effects such as vasorelaxant effect and negative inotropic effects. Moreover, SO2 might play considerable roles in the regulation of systemic circulatory pressure, pulmonary circulatory pressure and vascular structural remodeling in the pathogenesis of hypertension and hypoxic pulmonary hypertension. On the basis of the above findings, we presumed that endogenous SO2 might be a novel cardiovascular functional regulatory gasotransmitter. More studies on the significance of endogenous SO2 in cardiovascular system under physiological and pathophysiological conditions need to be investigated.展开更多
目的:分析体位性心动过速综合征(postural tachycardia syndrome, POTS)儿童及青少年直立试验过程中血流动力学变化及不同心脏指数(cardiac index, CI)患者血流动力学指标的差异。方法:回顾性分析26例POTS患者与12例健康对照者间直立试...目的:分析体位性心动过速综合征(postural tachycardia syndrome, POTS)儿童及青少年直立试验过程中血流动力学变化及不同心脏指数(cardiac index, CI)患者血流动力学指标的差异。方法:回顾性分析26例POTS患者与12例健康对照者间直立试验过程中总外周血管阻力指数(total peripheral vascular resistance index, TPVRI)、心率和血压的变化,并比较两组间各指标变化趋势。根据每位POTS患者直立试验过程中CI变化趋势将患者分为CI降低组(14例)与CI未降低组(12例),分析两组患者在直立试验过程中CI、TPVRI、心率、血压变化,并比较两组间各指标变化趋势。结果: POTS患者在直立试验过程中CI显著下降( F =6.936, P =0.001),心率明显增快( F = 113.926 , P <0.001),收缩压明显降低( F =6.049, P <0.001),而TPVRI ( F =2.031, P =0.138)和舒张压( F =2.018, P =0.113)无明显变化。健康对照组CI在直立后显著升高( F =3.646, P =0.016),同时心率明显增快( F = 43.970, P <0.001),收缩压( F =4.043, P =0.020)和舒张压( F =8.627, P <0.001)均明显升高,TPVRI ( F = 1.688, P =0.190)无明显变化。POTS患者与健康对照组比较,CI ( F =6.221, P= 0.001)、心率( F =6.203, P < 0.001)和收缩压( F =7.946, P <0.001)随时间变化趋势显著不同,而TPVRI和舒张压在两组间的变化趋势差异无统计学意义( P >0.05)。CI降低组与CI未降低组POTS患者在直立试验中CI变化趋势差异有统计学意义( F = 14.723, P <0.001),前者直立后收缩压明显降低( F =8.010, P <0.001),而后者却无明显变化( F =0.612, P = 0.639 ), TPVRI、心率和舒张压在CI降低组与CI未降低组间随时间变化趋势差异无统计学意义( P >0.05)。年龄是POTS患者直立后CI呈下降趋势的独立影响因素( P =0.013, OR =2.233;95% CI :1.183~4.216)。结论: POTS患者在直立试验过程中存在明显的血流动力学变化,不同患者心输出量变化可能不同,年龄是心输出量下降的独立影响因素。展开更多
目的构建载脂蛋白CⅢ(Apo CⅢ)转基因小鼠,并与动脉粥样硬化易感的低密度脂蛋白受体(LDLR)敲除小鼠杂交,获得Apo CⅢ转基因+LDLR缺陷(Apo CⅢ+LDLR^(―/―))小鼠模型,开展Apo CⅢ对动脉粥样硬化影响及潜在机制的研究。方法 Apo CⅢ+LDL...目的构建载脂蛋白CⅢ(Apo CⅢ)转基因小鼠,并与动脉粥样硬化易感的低密度脂蛋白受体(LDLR)敲除小鼠杂交,获得Apo CⅢ转基因+LDLR缺陷(Apo CⅢ+LDLR^(―/―))小鼠模型,开展Apo CⅢ对动脉粥样硬化影响及潜在机制的研究。方法 Apo CⅢ+LDLR^(―/―)小鼠与LDLR^(―/―)小鼠喂饲高脂饲料3个月,检测其血浆甘油三酯、总胆固醇、脂质过氧化产物和还原性谷胱甘肽水平。对小鼠的全主动脉和主动脉窦进行油红O染色及二氢乙啶染色,并提取主动脉的RNA和蛋白,分析相关基因的表达。结果 Apo CⅢ+LDLR^(―/―)小鼠喂饲高脂饲料后血浆甘油三酯水平明显高于LDLR^(―/―)小鼠,但总胆固醇水平差别不明显。主动脉全长和主动脉窦的染色显示动脉粥样硬化斑块明显增加。Apo CⅢ+LDLR^(―/―)小鼠血浆脂质过氧化产物8-异前列腺素和丙二醛水平明显升高,抗氧化物质还原性谷胱甘肽水平明显降低。对其主动脉进行二氢乙啶染色发现,动脉内活性氧水平明显增加。主动脉内氧化应激和内质网应激相关基因的mRNA和蛋白表达明显升高。提示Apo CⅢ可能通过增加动脉内的氧化应激和内质网应激,从而促进动脉粥样硬化斑块形成。结论 Apo CⅢ具有促动脉粥样硬化的作用,其机制可能与整体氧化应激水平的升高以及动脉壁氧化应激、内质网应激水平的增加有关。展开更多
文摘SUMMARY Since the 1980 s nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), the endogenous gas molecules produced from metabolic pathway, have been realized as signal molecules to be involved in the regulation of body homeostasis and to play important roles under physiological and pathophysiological conditions. The researches on these endogenous gas signal molecules opened a new avenue in life science. To explore the new member of gasotransmitter family, other endogenous gas molecules which have been regarded as metabolic waste up to date, and their biological regulatory effects have been paid close attention to in the current fields of life science and medicine. Sulfur dioxide (SO2) can be produced endogenously from normal metabolism of sulfur-containing amino acids. L-cysteine is oxidized via cysteine dioxygenase to L-cysteinesulfinate, and the latter can proceed through transamination by glutamate oxaloacetate transaminase (GOT) to β-sulfinylpyruvate which decomposes spontaneously to pyruvate and SO2. In mammals, activated neutrophils by oxidative stress can convert H2S to sulfite through a reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase-dependent process. The authors detected endogenous production of SO2 in all cardiovascular tissues, including in heart, aorta, pulmonary artery, mesenteric artery, renal artery, tail artery and the plasma SO2 content. As the key enzyme producing SO2, GOT mRNA in cardiovascular system was detected and found to be located enrichedly in endothelial cells and vascular smooth muscle cells near the endothelial layer.When the normal rats were treated with hydroxamate(HDX), a GOT inhibitor, at a dose of 3.7 mg/kg body weight, the blood pressure (BP) went high markedly, the ratio of wall thickness to lumen radius was increased by 18.34%, and smooth muscle cell proliferation was enhanced. The plasma SO2 level in the rats injected with 125 μmol/kg body weight SO2 donor was increased to 721.98±30.11 μmol/L at the end of 30 seconds, while the blood pressure was decreased to the lowest point 65.0± 4.9 mm Hg at the end of 1 minute. The above results showed that endogenous SO2 might be involved in the maintenance of blood pressure and normal vascular structure. In spontaneous hypertensive rat (SHR) animal model, exogenous supplement of SO2 donor decreased the BP, the media cross-sectional area, and pressure of the media and the ratio of wall thickness to lumen radius in the SHR. Moreover, the proliferative index of aortic smooth muscle cells was decreased in the SHR treated with SO2 donor compared with that in SHR. The above data showed that SO2 could prevent the aortic structural remodeling by inhibiting the proliferation of aortic smooth muscle cells.The authors observed the direct vasorelaxant effects of SO2 on the aortic ring pre-treated with norepinephrin (NE). SO2 donor at a concentration of 25—100 μmol/L relaxed the aortic ring temporarily and slightly, but SO2 donor at a concentration of 1—12 mmol/L induced relaxation of the ring in a concentration-dependent manner. Administration with nicardipine, an L-type calcium channel blocker other than glibenclamide, an ATP sensitive potassium channel (KATP channel) blocker or removal of vascular endothelium could decrease the SO2-induced vasorelaxation. In hypoxic pulmonary hypertension animal model, SO2 donor decreased the mean pulmonary artery pressure and the systolic pulmonary artery pressure (P<0.01), respectively as compared with hypoxic group, and alleviated obviously the hypoxic pulmonary vascular structural remodeling. The percentage of muscularized arteries of small pulmonary vessels was significantly decreased in hypoxia+SO2 donor-treated rats compared with that of hypoxic rats (P<0.01), while the percentage of non-muscularized vessels was obviously higher in hypoxia with SO2 donor-treated rats than that of hypoxic rats (P<0.01). Similarly, SO2 obviously decreased relative media area and relative media thickness of small muscularized pulmonary arteries in hypoxic rats (P<0.01). The above data showed that SO2 might play an important role in development of hypoxic pulmonary hypertension.Perfusion with SO2 donor (10-6—10-3 mol/L) to the isolated rat heart obviously inhibited the left ventricular peak rate of contraction ( + LV dp/ dtmax) , peak rate of relaxation ( -LV dp/ dtmax) and difference of left ventricular pressure ( ΔLVP) in a concentration dependent manner. Nicardipine, an L-type calcium channel blocker, could partly antagonize the inhibitory effect of SO2 on the heart function. In a word, SO2 could be endogenously generated in cardiovascular tissues and exert important cardiovascular effects such as vasorelaxant effect and negative inotropic effects. Moreover, SO2 might play considerable roles in the regulation of systemic circulatory pressure, pulmonary circulatory pressure and vascular structural remodeling in the pathogenesis of hypertension and hypoxic pulmonary hypertension. On the basis of the above findings, we presumed that endogenous SO2 might be a novel cardiovascular functional regulatory gasotransmitter. More studies on the significance of endogenous SO2 in cardiovascular system under physiological and pathophysiological conditions need to be investigated.
文摘目的:分析体位性心动过速综合征(postural tachycardia syndrome, POTS)儿童及青少年直立试验过程中血流动力学变化及不同心脏指数(cardiac index, CI)患者血流动力学指标的差异。方法:回顾性分析26例POTS患者与12例健康对照者间直立试验过程中总外周血管阻力指数(total peripheral vascular resistance index, TPVRI)、心率和血压的变化,并比较两组间各指标变化趋势。根据每位POTS患者直立试验过程中CI变化趋势将患者分为CI降低组(14例)与CI未降低组(12例),分析两组患者在直立试验过程中CI、TPVRI、心率、血压变化,并比较两组间各指标变化趋势。结果: POTS患者在直立试验过程中CI显著下降( F =6.936, P =0.001),心率明显增快( F = 113.926 , P <0.001),收缩压明显降低( F =6.049, P <0.001),而TPVRI ( F =2.031, P =0.138)和舒张压( F =2.018, P =0.113)无明显变化。健康对照组CI在直立后显著升高( F =3.646, P =0.016),同时心率明显增快( F = 43.970, P <0.001),收缩压( F =4.043, P =0.020)和舒张压( F =8.627, P <0.001)均明显升高,TPVRI ( F = 1.688, P =0.190)无明显变化。POTS患者与健康对照组比较,CI ( F =6.221, P= 0.001)、心率( F =6.203, P < 0.001)和收缩压( F =7.946, P <0.001)随时间变化趋势显著不同,而TPVRI和舒张压在两组间的变化趋势差异无统计学意义( P >0.05)。CI降低组与CI未降低组POTS患者在直立试验中CI变化趋势差异有统计学意义( F = 14.723, P <0.001),前者直立后收缩压明显降低( F =8.010, P <0.001),而后者却无明显变化( F =0.612, P = 0.639 ), TPVRI、心率和舒张压在CI降低组与CI未降低组间随时间变化趋势差异无统计学意义( P >0.05)。年龄是POTS患者直立后CI呈下降趋势的独立影响因素( P =0.013, OR =2.233;95% CI :1.183~4.216)。结论: POTS患者在直立试验过程中存在明显的血流动力学变化,不同患者心输出量变化可能不同,年龄是心输出量下降的独立影响因素。
文摘目的构建载脂蛋白CⅢ(Apo CⅢ)转基因小鼠,并与动脉粥样硬化易感的低密度脂蛋白受体(LDLR)敲除小鼠杂交,获得Apo CⅢ转基因+LDLR缺陷(Apo CⅢ+LDLR^(―/―))小鼠模型,开展Apo CⅢ对动脉粥样硬化影响及潜在机制的研究。方法 Apo CⅢ+LDLR^(―/―)小鼠与LDLR^(―/―)小鼠喂饲高脂饲料3个月,检测其血浆甘油三酯、总胆固醇、脂质过氧化产物和还原性谷胱甘肽水平。对小鼠的全主动脉和主动脉窦进行油红O染色及二氢乙啶染色,并提取主动脉的RNA和蛋白,分析相关基因的表达。结果 Apo CⅢ+LDLR^(―/―)小鼠喂饲高脂饲料后血浆甘油三酯水平明显高于LDLR^(―/―)小鼠,但总胆固醇水平差别不明显。主动脉全长和主动脉窦的染色显示动脉粥样硬化斑块明显增加。Apo CⅢ+LDLR^(―/―)小鼠血浆脂质过氧化产物8-异前列腺素和丙二醛水平明显升高,抗氧化物质还原性谷胱甘肽水平明显降低。对其主动脉进行二氢乙啶染色发现,动脉内活性氧水平明显增加。主动脉内氧化应激和内质网应激相关基因的mRNA和蛋白表达明显升高。提示Apo CⅢ可能通过增加动脉内的氧化应激和内质网应激,从而促进动脉粥样硬化斑块形成。结论 Apo CⅢ具有促动脉粥样硬化的作用,其机制可能与整体氧化应激水平的升高以及动脉壁氧化应激、内质网应激水平的增加有关。
