Sulfhydration-associated phosphodiesterase 5A dimerization mediates vasorelaxant effect of hydrogen sulfide

Abstract

// Yan Sun 1, * , Yaqian Huang 1, * , Wen Yu 1, * , Siyao Chen 2 , Qiuyu Yao 1 , Chunyu Zhang 1 , Dingfang Bu 3 , Chaoshu Tang 4 , Junbao Du 1, 5 , Hongfang Jin 1 1 Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China 2 Department of Cardiac Surgery, Guangdong General Hospital, Guangzhou, 510000, China 3 Centre Laboratory of Peking University First Hospital, Beijing, 100034, China 4 Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100034, China 5 Key Laboratory of Cardiovascular Sciences, Ministry of Education, Beijing, 100034, China * These authors contributed equally to this work Correspondence to: Hongfang Jin, email: jinhongfang51@126.com Keywords: hydrogen sulfide, sGC/PDE/cGMP/PKG, dimer, sulfhydrylation Received: August 20, 2016      Accepted: March 16, 2017      Published: March 29, 2017 ABSTRACT The study was designed to examine if the vasorelaxant effect of hydrogen sulfide was mediated by sulfhydration-associated phosphodiesterase (PDE) 5A dimerization. The thoracic aorta of rat was separated and the vasorelaxant effects were examined with in vitro vascular perfusion experiments. The dimerization and sulfhydration of PDE 5A and soluble guanylatecyclase (sGC) were measured. PDE 5A and protein kinase G (PKG) activities were tested. Intracellular cGMP content was detected by enzyme-linked immunosorbent assay (ELISA). The results showed that NaHS relaxed isolated rat vessel rings at an EC50 of (1.79 ± 0.31)×10 −5 mol/L, associated with significantly increased PKG activity and cGMP content in vascular tissues. Sulfhydration of sGC β1 was increased, while the levels of sGC αβ1 dimers were apparently decreased after incubation with NaHS in vascular tissues. Moreover, PDE 5A homodimers were markedly decreased, and accordingly the PDE 5A activity demonstrated by the content of 5′-GMP was significantly decreased after incubation with NaHS or GYY4137. Mechanistically, both NaHS and GYY4137 significantly enhanced the PDE 5A sulfhydration in vascular tissues. DTT partially abolished the effects of NaHS on PDE 5A activity, cGMP content and vasorelaxation. Therefore, the present study for the first time suggested that H 2 S exerted vasorelaxant effect probably via sulfhydration-associated PDE 5A dimerization.