Endogenous hydrogen sulfide is involved in the pathogenesis of atherosclerosis.

Atherosclerosis is a chronic, complex, and progressive pathological process in large and medium sized arteries. The exact mechanism of this process remains unclear. Hydrogen sulfide (H(2)S), a novel gasotransmitter, was confirmed as playing a major role in the pathogenesis of many cardiovascular diseases. It plays a role in vascular smooth muscle cell (VSMC) proliferation and apoptosis, participates in the progress of hyperhomocysteinemia (HHCY), inhibits atherogenic modification of LDL, interferes with vascular calcification, intervenes with platelet function, and there are interactions between H(2)S and inflammatory processes. The role of H(2)S in atherosclerotic pathogenesis highlights the mysteries of atherosclerosis and inspires the search for innovative therapeutic strategies. Here, we review the studies to date that have considered the role of H(2)S in atherosclerosis.

Profiles of levels of lipids and dyslipidaemia in children from Beijing, China.

BACKGROUND: There is limited data available on characteristics of profiles of lipids in children. The purpose of our investigation, therefore, was to determine the lipid profile, and analyze the prevalence of dyslipidaemia, in subgroups of children according to different gender, districts of residence, and ages in Beijing, China. METHODS AND RESULTS: We included 18,944 school children, aged from 7 to 18 years, in our community-based cross-sectional study, measuring the levels of total cholesterol and triglyceride in capillary blood, and at the same time determining their weight and height. Weights, heights, circumference at the waist, and body mass index proved to be significantly greater for the boys than the girls. The levels of total cholesterol of boys and girls were 3.98 +/- 0.35, and 4.02 +/- 0.35 mmol/L, respectively, while the comparable levels of triglycerides were 1.08 +/- 0.52, and 1.18 +/- 0.66 mmol/L, respectively. The percentages of hypercholesterolaemia, hypertriglyceridaemia, combined dyslipidaemia, and hyperlipidaemia were 1.2, 8.8, 0.4, and 9.7%, respectively. The incidences of hypertriglyceridaemia, combined dyslipidaemia, and hyperlipidaemia of girls were higher than boys. The levels of triglycerides for boys aged from 11 to 18 years living in an urban setting were higher than those for boys living in rural settings, as were the levels of total cholesterol for boys aged from 12 to 16 years. CONCLUSION: Our study provides the newest current profiles of lipids for children living in Beijing. We found significant influences of age, districts of residence, and genders on the levels of lipids, features which need further attention in the prevention and treatment of dyslipidaemia.

The efficacy of midodrine hydrochloride in the treatment of children with vasovagal syncope.

OBJECTIVE: To determine whether midodrine hydrochloride therapy can prevent vasovagal syncope (VVS) in pediatric patients. STUDY DESIGN: Children with recurrent syncope (n = 26) were randomly assigned into 2 groups. Group I comprised children given midodrine hydrochloride as first-line therapy in addition to conventional therapy, and group II comprised patients receiving conventional therapy only. Repeat head-up tilt (HUT) testing and follow-up of least 6 months were conducted to evaluate the therapeutic effectiveness and side effects of midodrine in treating VVS in children. RESULTS: The HUT-based effective rate was significantly higher in group I than in group II (75% vs 20%; P < .05). During the follow-up period, the recurrence of syncope was significantly lower in group I than in group II (P < .05). CONCLUSIONS: Midodrine hydrochlorate is effective in treating VVS in children, especially in preventing recurrent episodes. Few side effects were observed in the present study.

Impact of L-arginine on hydrogen sulfide/cystathionine-gamma-lyase pathway in rats with high blood flow-induced pulmonary hypertension.

The present study was designed to explore the possible effect of L-arginine on endogenous hydrogen sulfide/cystathionine-gamma-lyase (H(2)S/CSE) pathway in the pathogenesis of pulmonary hypertension and pulmonary vascular structural remodeling induced by high pulmonary blood flow. Thirty-two male Sprague-Dawley rats were randomly divided into control group (n=11), shunt group (n=11) and shunt with L-arginine group (n=10). Rats in the shunt and shunt with L-arginine group underwent an abdominal aorta-inferior cava vein shunt operation. After 11 weeks of shunting, the plasma level of H2S and lung tissue H2S production rate in the shunt with L-arginine group were much higher than those in the shunt group (P<0.01). Meanwhile, the expression of CSE mRNA in the lung tissues of rats in the shunt with L-arginine group was increased significantly (P<0.01), and in situ hybridization showed that CSE mRNA expression was obviously up-regulated in the smooth muscle cells (SMCs) of the pulmonary arteries of shunted rats treated with L-arginine when compared with shunted rats without the treatment of L-arginine (P<0.01). In conclusion, H2S/CSE pathway was up-regulated by L-arginine in pulmonary hypertension induced by high blood flow with the attenuation of pulmonary hypertension and pulmonary vascular structural remodeling.

Inhalation of nebulized nitroglycerin, a nitric oxide donor, for the treatment of pulmonary hypertension induced by high pulmonary blood flow.

This study explores the effect and mechanisms of inhalation of nebulized nitroglycerin (Neb-NTG) on pulmonary hypertension induced by high pulmonary blood flow. An aortocaval shunt was produced in rats. Twelve weeks after the operation, rats started to inhale Neb-NTG. After 15 weeks, pulmonary and systemic hemodynamics as well as pathological changes were measured in all animals. Inhalation of Neb-NTG was able not only to markedly attenuate pulmonary artery pressure without impacting systolic pressure but also to ameliorate muscularization of small pulmonary arteries. The relaxation response of pulmonary artery ring to acetylcholine in shunt rats and Neb-NTG-treated rats was decreased. However, Neb-NTG did not impact the relaxation response of pulmonary artery ring to both nitroprusside and nitroglycerin (NTG). Neb-NTG successfully inhibited the increased expression of pulmonary artery smooth muscle cell (PASMC) proliferative cell nuclear antigen, collagen I, and collagen III, as well as pulmonary artery urotensin-II in shunt rats with high pulmonary blood flow. Neb-NTG selectively ameliorated pulmonary hypertension as well as pulmonary vascular structural remodeling induced by high pulmonary blood flow.

Down-regulation of endogenous hydrogen sulfide pathway in pulmonary hypertension and pulmonary vascular structural remodeling induced by high pulmonary blood flow in rats.

BACKGROUND: The mechanisms responsible for the development of pulmonary hypertension (PH) and pulmonary vascular structural remodeling induced by high pulmonary blood flow are not fully understood. The present study was designed to explore the possible changes in endogenous hydrogen sulfide (H2S), a novel gasotransmitter, on the pathogenesis of PH and pulmonary vascular structural remodeling induced by high pulmonary blood flow. METHODS AND RESULTS: Twenty-two male Sprague-Dawley rats were randomly divided into a shunting group (n=11) and control group (n=11). Rats in the shunting group underwent an abdominal aorta-inferior cava vein shunting operation. After 11 weeks of shunting, the plasma level of H2S and lung tissue H2S producing rate were much lower than those of the control group (p<0.01). In situ hybridization analysis showed that the expression of cystathionine gamma-lyase (CSE) mRNA was down-regulated in the pulmonary arteries of the shunting rats compared with the control group (p<0.01), and competitive quantitative reverse transcription-polymerase chain reaction showed that the relative amount of CSEmRNA in lung tissue was decreased significantly (p<0.01). CONCLUSIONS: The endogenous H2S pathway is down-regulated in PH and pulmonary vascular structural remodeling is induced by high pulmonary blood flow.

Effect of L-arginine on collagen of high flow-induced pulmonary arterial remodeling.

BACKGROUND: Pulmonary hypertension (PH) is a common complication of congenital heart disease and pulmonary vascular structural remodeling due to the high pulmonary blood flow is considered as the key pathologic process. In the present study the effects of L-arginine on the collagen metabolism of pulmonary arteries in rats with high pulmonary blood flow-induced PH were investigated to elucidate its mechanism. METHODS AND RESULTS: The rat model of PH was established with an abdominal aorta and inferior vena cava shunt. L-arginine (1 g/kg per day) was given directly into the stomachs of the rats with the shunt (L-arginine+shunt group) and 11 weeks later, the pulmonary hemodynamics were studied. Collagen I and collagen III expressions were detected by immunohistochemical assay. The expressions of procollagen I mRNA, procollagen III mRNA, the tissue inhibitor of metalloproteinase-1 mRNA and the matrix metalloproteinase-1 mRNA were detected by in situ hybridization. The expressions of pulmonary artery collagen I, collagen III, procollagen I mRNA and procollagen III mRNA in the shunt rats were obviously elevated compared with the control rats (p<0.01). The positive signals were mainly located in the media and adventitia of median and small pulmonary arteries. The expressions of the pulmonary artery tissue inhibitor of metalloproteinase-1 mRNA, metalloproteinase-1 mRNA and the ratio of tissue inhibitor of metalloproteinase-1/metalloproteinase-1 were elevated in the shunt rats (p<0.01). However, the expressions of pulmonary artery collagen I, collagen III, procollagen I mRNA and procollagen III mRNA were significantly reduced in the shunt rats of the L-arginine group (p<0.01). L-arginine also downregulated the expressions of tissue inhibitor of metalloproteinase-1 mRNA and metalloproteinase-1 mRNA, as well as the ratio of tissue inhibitor of metalloproteinase-1/metalloproteinase-1 (p<0.05). CONCLUSIONS: L-arginine can reduce the synthesis of extracellular matrix-collagen and increase its degradation, thus having an important modulating effect on pulmonary vascular matrix remodeling induced by high pulmonary blood flow.

Impact of hydrogen sulfide on carbon monoxide/heme oxygenase pathway in the pathogenesis of hypoxic pulmonary hypertension.

Hypoxic pulmonary hypertension (HPH) is an important pathophysiological process of a variety of cardiac and pulmonary diseases. But the mechanisms responsible for HPH are still not fully understood. The discoveries of endogenous gas signal molecules, nitric oxide (NO), and carbon monoxide (CO), have been moving the research of HPH to a new phase. Hydrogen sulfide (H2S), which is now being considered as the third new gas transmitter, was found to be possibly involved in the pathogenesis of HPH. But whether there exists an interaction between H2S and CO has not been clear in the pathogenesis of HPH. In this study, we found that H2S was significantly decreased in the pathogenesis of HPH. However, plasma CO level and the expressions of heme oxygenase (HO-1) protein and HO-1 mRNA were significantly increased. Exogenous supply of H2S could alleviate the elevation of pulmonary arterial pressure. At the same time, plasma CO level and the expressions of HO-1 protein and mRNA in pulmonary arteries were significantly increased. Whereas, exogenous supply of propargylglycine (PPG), an inhibitor of cystathionine gamma-lyase (CSE), decreased the plasma H2S content and worsened HPH. At the same time, plasma CO level and the expressions of HO-1 protein and mRNA in pulmonary arteries were decreased. The results showed that H2S could play a regulatory role in the pathogenesis of HPH through up-regulating CO/HO pathway.

The regulating effect of heme oxygenase/carbon monoxide on hypoxic pulmonary vascular structural remodeling.

Hypoxic pulmonary vascular structural remodeling (HPVSR) is the important pathologic basis of hypoxic pulmonary hypertension (HPH). The discoveries of endogenous gaseous messenger molecules, nitric oxide (NO) and carbon monoxide (CO), have been moving the research of HPVSR to a very new phase. But the effect and significance of heme oxygenase (HO)/CO on the development of HPVSR have not been fully understood. In this study, we observed the alteration of endogenous HO/CO system in five time points during 14 days and found that the content of CO in lung homogenates in rats with HPVSR increased in a time-dependent double-peak manner. Exogenous supply of ZnPP-IX, an inhibitor of HO-1, decreased the content of CO in lung homogenate, decreased the expression of Fas and apoptotic cells in pulmonary artery smooth muscle cells (PASMCs), up-regulated the expression of PCNA in PASMCs, and worsened HPH and HPVSR of hypoxic rats. Meanwhile, exogenous supply of CO played an adverse action. The results showed that the up-regulation of HO/CO exerted a protective role in the development of HPVSR.

The regulatory effect of hydrogen sulfide on hypoxic pulmonary hypertension in rats.

Hypoxic pulmonary hypertension (HPH) is an important pathophysiological process. The mechanism of HPH is still not fully understood. Recent studies showed that hydrogen sulfide (H(2)S) could relax vascular smooth muscles and inhibit the proliferation of cultured vascular smooth muscle cells. Our study showed that both the gene expression of cystathionine gamma-lyase (CSE), one of the H(2)S generating enzymes, and the activity of CSE were suppressed in lung tissues during HPH. And the plasma level of H(2)S was decreased during HPH. Exogenous supply of H(2)S could increase the plasma level of H(2)S, enhance CSE activity, and up-regulate CSE gene expression in lung tissue. At the same time, exogenous supply of H(2)S could oppose the elevation of pulmonary arterial pressure and lessen the pulmonary vascular structure remodeling during HPH. The results showed that endogenous H(2)S system was involved and exogenous H(2)S could exert beneficial effect on the pathogenesis of HPH.

L-arginine impacts pulmonary vascular structure in rats with an aortocaval shunt.

BACKGROUND: The present study was designed to explore the therapeutic effect of L-arginine on the proliferation and apoptosis of pulmonary artery smooth muscle cells (SMCs) in high pulmonary blood flow-induced pulmonary hypertension and therefore to provide a basis for the mechanism by which L-arginine regulated pulmonary hypertension. MATERIALS AND METHODS: Twenty-one male SD rats were randomly divided into shunting group, shunting with L-arginine group, and control group. Abdominal aorta and inferior vena cava shunting was produced in rats of the shunting group and the shunting with L-arginine group. Pulmonary artery mean pressure (mPAP) and pulmonary vascular microstructure were analyzed. Immunohistochemistry for proliferative cell nuclear antigen (PCNA) and Fas expressions and TdT-mediated dUTP-biotin nick-end labeling (TUNEL) were used to detect cell proliferation and apoptosis, respectively. RESULTS: mPAP, RV/BW, and RV/LV + S were significantly increased in shunted rats compared to normal controls (P < 0.01, respectively). Pulmonary vascular structural remodeling developed in shunted rats. Proliferative index (PI), apoptotic index (AI), and the ratio of PI/AI of pulmonary artery SMCs in the rats of shunting group were elevated obviously (P < 0.01). Meanwhile, the expressing integral score of Fas was elevated in the shunting group (P < 0.01). However, L-arginine significantly attenuated pulmonary artery pressure and ameliorated pulmonary vascular structural remodeling. Also, it reduced PI and again augmented AI of pulmonary artery SMCs. The ratio of PI/AI was significantly reduced (P < 0.01). The expressing integral score of Fas was again augmented by L-arginine (P < 0.01). CONCLUSIONS: L-Arginine could inhibit proliferation and promote apoptosis of pulmonary artery SMCs in shunted rats.

Signaling pathway of cardioprotection induced by monophosphoryl lipid A in rabbit myocardium.

OBJECTIVE: To investigate the effect of monophosphoryl lipid A (MLA) on ischemia/reperfusion (I/R) injury in rabbit heart and its signal transduction pathway. METHODS: Eighteen rabbits were randomly assigned to three groups: (1) MLA-group: Six rabbits received injection of MLA (35 &mgr;g/kg, iv) 24 h prior to 45 min of ischemia followed by 60 min of reperfusion. (2) Control group: Six rabbits received an intravenous bolus injection of the same volume of vehicle. (3) SB group: Six rabbits intravenously received 2 &mgr;mol/l SB 203580 30-min prior to MLA administration. At the end of reperfusion, myocardial infarct size and serum nitrite/nitrate were detected. Myocardium p38 mitogen-activated protein kinase (p38 MAPK) was detected using a Western blotting method. RESULTS: MLA pretreatment caused a significant reduction of infarct size as percent of area at risk as compared to vehicle-pretreated controls (36+/-3 vs. 65+/-4%, P<0.001). Total nitrite in serum increased in MLA pretreated animals (P<0.05). The protective effects of MLA were completely abolished by selective p38 MAPK inhibitor SB 203580. Western blot analysis showed significant accumulations of p38 MAPK proteins in the myocardium of MLA pretreated animals. CONCLUSIONS: MLA can protect the heart by reducing myocardial infarct size in rabbits. This cardioprotective effect might be attributed to upregulation of nitric oxide (NO) through the activation of p38 MAPK.