Bench to beside: the imbalance of mutual regulation of homocysteine and hydrogen sulfide in congenital heart disease related pulmonary arterial hypertension

【摘要】 Background To determine the imbalance of mutual regulation of homocysteine and hydrogen sulfide（H₂S） in congenital heart disease（CHD）-related pulmonary arterial hypertension（PAH） among pediatric patients, and explore possible mechanisms. Methodology and Principal Findings: In this study, we regulated homocysteine concentrations to observe the relations between homocysteine and H₂S. Cell viability and activity of metabolic enzymes were determined. Cytological experiments demonstrated that exogenous or endogenous H₂S both had protective effects on HPAECs and can inhibit homocysteine-induced apoptosis. The possible mechanisms were correlated with GRP78 and CHOP expressions of endoplasmic reticulum stress pathway. In addtion, we found that homocysteine and H₂S were in a dynamic change, which was related to the homocysteine concentration. When the homocysteine concentrations were low（≤30 μmol/L）, the protective effects of H₂S can resist the homocysteine-induced damage effects. However, the cytological results were different from the clinical data. Our clinical study had showed that the levels of homocysteine were higher, the levels of H₂S and the OD values of cystathionine gamma-lyase（CSE） were lower in the PAH group. All the CHD-PAH patients had low homocysteine（≤30 μmol/L） concentrations still lead to PAH because of decreased the protective effects of H₂S due to the decreased activity of CSE. Conclusion: Homocysteine and H₂S both take part in the development of CHD-PAH. Hyperhomocysteinemia may be the pathogenic factor, while H₂S is the protective factor. The mutual dynamic regulations are related to the homocysteine concentration. The clinical trials and cytological experiment results have great implications for clinical practice. For patients with PAH, not only the damage of homocysteine to endothelial cells, but also we should pay attention to the decreased protection of H₂S and activity of metabolic enzymes.[S Chin J Cardiol 2022;23（1）:39 - 52］更多还原

【Abstract】 Background To determine the imbalance of mutual regulation of homocysteine and hydrogen sulfide（H₂S） in congenital heart disease（CHD）-related pulmonary arterial hypertension（PAH） among pediatric patients, and explore possible mechanisms. Methodology and Principal Findings: In this study, we regulated homocysteine concentrations to observe the relations between homocysteine and H₂S. Cell viability and activity of metabolic enzymes were determined. Cytological experiments demonstrated that exogenous or endogenous H₂S both had protective effects on HPAECs and can inhibit homocysteine-induced apoptosis. The possible mechanisms were correlated with GRP78 and CHOP expressions of endoplasmic reticulum stress pathway. In addtion, we found that homocysteine and H₂S were in a dynamic change, which was related to the homocysteine concentration. When the homocysteine concentrations were low（≤30 μmol/L）, the protective effects of H₂S can resist the homocysteine-induced damage effects. However, the cytological results were different from the clinical data. Our clinical study had showed that the levels of homocysteine were higher, the levels of H₂S and the OD values of cystathionine gamma-lyase（CSE） were lower in the PAH group. All the CHD-PAH patients had low homocysteine（≤30 μmol/L） concentrations still lead to PAH because of decreased the protective effects of H₂S due to the decreased activity of CSE. Conclusion: Homocysteine and H₂S both take part in the development of CHD-PAH. Hyperhomocysteinemia may be the pathogenic factor, while H₂S is the protective factor. The mutual dynamic regulations are related to the homocysteine concentration. The clinical trials and cytological experiment results have great implications for clinical practice. For patients with PAH, not only the damage of homocysteine to endothelial cells, but also we should pay attention to the decreased protection of H₂S and activity of metabolic enzymes.[S Chin J Cardiol 2022;23（1）:39 - 52］更多还原