Norswertianolin Promotes Cystathionine γ-Lyase Activity and Attenuates Renal Ischemia/Reperfusion Injury and Hypertension.

Yaping Niu,Jun Cai,Yue Deng,Congkuo Du,Bin Geng,Changting Cui,Zhenzhen Chen,Haizeng Zhang

doi:10.3389/fphar.2021.677212

Abstract

Cystathionine gamma-lyase (CSE)/hydrogen sulfide (H2S) plays a protective role in cardiovascular diseases including hypertension and ischemia/reperfusion (I/R) injury. This study was aimed to screen natural small molecule compounds that activate CSE activity and then evaluate its effect(s) on kidney I/R injury and hypertension. Applying computer molecular docking technology, we screened the natural small molecule compound norswertianolin (NW)-specific binding to CSE. Using the microscale thermophoresis technology, we confirmed that the Leu68 site was the essential hydrogen bond site of NW binding to CSE. NW supplementation significantly increased CSE expression and its activity for H2S generation both in vivo and in vitro. In the model of acute and long-term kidney I/R injury, NW pretreatment dramatically attenuated kidney damage, associated with decreasing blood urea nitrogen (BUN), serum creatinine (Cr) level, reactive oxygen species (ROS) production, and cleaved caspase 3 expression. In spontaneously hypertensive rats (SHRs), NW treatment also lowered blood pressure, the media/lumen ratio of the femoral artery, and the mRNA level of inflammatory cytokines. In conclusion, NW acts as a novel small molecular chemical compound CSE agonist, directly binding to CSE, heightening CSE generation–H2S activity, and then alleviating kidney I/R injury and hypertension. NW has a potential therapeutic merit for cardiovascular diseases.

Highlights

More and more studies demonstrate that hydrogen sulfide (H2S), as a third gasotransmitter, exhibits critical physiological and pathophysiological roles in cerebrovascular diseases (Paul and Snyder, 2018), pulmonary vascular diseases (Chunyu et al, 2003), and cardiovascular diseases (Yu et al, 2014; Pan et al, 2017)
Based on the 3D structure of human Cystathionine gamma-lyase (CSE) (Figure 1A) from the Protein Data Bank, we screened a natural small molecule norswertianolin (NW) (Figure 1B) from the Chinese Natural Products Database (CNPD), which had high affinity binding to CSE using computer molecular docking technology
More and more studies focus on H2S donor development, design, and synthesis, such as GYY4137, SG1002, and ATB-346

Summary

Introduction

More and more studies demonstrate that hydrogen sulfide (H2S), as a third gasotransmitter, exhibits critical physiological and pathophysiological roles in cerebrovascular diseases (Paul and Snyder, 2018), pulmonary vascular diseases (Chunyu et al, 2003), and cardiovascular diseases (Yu et al, 2014; Pan et al, 2017). Hydrogen sulfide is metabolized from cysteine by enzymatic reaction in the presence of cystathionine-c-lyase (CSE), cystathionine-β-synthetase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST). CBS is present mostly in the central nervous system, while CSE is mainly expressed in the cardiovascular system (Predmore et al, 2012). A Novel Agonist of Cystathionine γ-Lyase and CBS, CSE contributed 90% H2S production (Singh and Banerjee, 2011). It is a promising therapeutic strategy to supplement H2S-releasing donors or CSE agonists. H2S donors such as sulfide salts (Na2S, NaHS), GYY4137, and 5-(4-

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