Compensatory role of endogenous sulfur dioxide in nitric oxide deficiency-induced hypertension
Yunjia Song,
Jiaru Song,
Zhigang Zhu,
Hanlin Peng,
Xiang Ding,
Fuquan Yang,
Kun Li,
Xiaoqi Yu,
Guosheng Yang,
Yinghong Tao,
Dingfang Bu,
Chaoshu Tang,
Yaqian Huang,
Junbao Du,
Hongfang Jin
Affiliations
Yunjia Song
Department of Pediatrics, Peking University First Hospital, Beijing, China
Jiaru Song
Department of Pediatrics, Peking University First Hospital, Beijing, China
Zhigang Zhu
Department of Pediatrics, Peking University First Hospital, Beijing, China
Hanlin Peng
Department of Pediatrics, Peking University First Hospital, Beijing, China
Xiang Ding
Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
Fuquan Yang
Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
Kun Li
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, China
Xiaoqi Yu
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, China
Guosheng Yang
Laboratory Animal Facility, Peking University First Hospital, Beijing, 100034, China
Yinghong Tao
Laboratory Animal Facility, Peking University First Hospital, Beijing, 100034, China
Dingfang Bu
Central Laboratory, Peking University First Hospital, Beijing, 100034, China
Chaoshu Tang
Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing, China
Yaqian Huang
Department of Pediatrics, Peking University First Hospital, Beijing, China
Junbao Du
Department of Pediatrics, Peking University First Hospital, Beijing, China; Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing, China
Hongfang Jin
Department of Pediatrics, Peking University First Hospital, Beijing, China; Corresponding author. Department of Pediatrics, Peking University First Hospital, No. 1, Xi'an-men Street, West District, Beijing, 100034, China.
Objective: This study aimed to determine the communicational pattern of gaseous signaling molecules sulfur dioxide (SO2) and nitric oxide (NO) between vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), and elucidate the compensatory role and significance of endogenous SO2 in the development of hypertension due to NO deficiency. Approach and results: Blood pressure was monitored by the tail-cuff and implantable physiological signal telemetry in L-nitro-arginine methyl ester (l-NAME)-induced hypertensive mice, and structural alterations of mouse aortic vessels were detected by the elastic fiber staining method. l-NAME-treated mice showed decreased plasma NO levels, increased SO2 levels, vascular remodeling, and increased blood pressure, and application of l-aspartate-β-hydroxamate, which inhibits SO2 production, further aggravated vascular structural remodeling and increased blood pressure. Moreover, in a co-culture system of HAECs and HASMCs, NO from HAECs did not influence aspartate aminotransferase (AAT)1 protein expression but decreased AAT1 activity in HASMCs, thereby resulting in the inhibition of endogenous SO2 production. Furthermore, NO promoted S-nitrosylation of AAT1 protein in HASMCs and purified AAT1 protein. Liquid chromatography with tandem mass spectrometry showed that the Cys192 site of AAT1 purified protein was modified by S-nitrosylation. In contrast, dithiothreitol or C192S mutations in HASMCs blocked NO-induced AAT1 S-nitrosylation and restored AAT1 enzyme activity. Conclusion: Endothelium-derived NO inhibits AAT activity by nitrosylating AAT1 at the Cys192 site and reduces SO2 production in HASMCs. Our findings suggest that SO2 acts as a compensatory defense system to antagonize vascular structural remodeling and hypertension when the endogenous NO pathway is disturbed.
