Vascular Protection of Hydrogen Sulfide on Cerebral Ischemia/Reperfusion Injury in Rats

Abstract

This study was undertaken to demonstrate the vascular protection of exogenous and endogenous hydrogen sulfide (H2S) on cerebral ischemia/reperfusion (I/R) injury. The effect of H2S on cerebrovascular dysfunction in middle cerebral artery (MCA) and neuronal damage were measured after cerebral I/R induced by transient middle cerebral artery occlusion (MCAO) in cystathionine c-lyase (CSE) knockdown and wild-type rats. The effect of sodium hydrosulfide (NaHS, donor of exogenous H2S), L-cysteine (L-Cys, substrate of endogenous H2S), and endothelium cells on the responses of isolated MCA derived from non-ischemic rats was also evaluated to assess the underlying mechanism of H2S-mediate cerebral vasodilation. The results revealed that the contraction and dilation of MCA profoundly decreased after cerebral I/R. The vascular dysfunction became more grievous in CSE knockdown rats than in wild-type rats. Interestingly, this vascular dysfunction was significantly alleviated by NaHS supplementation. Moreover, both NaHS and L-cysteine could induce remarkable relaxation in the isolated MCA, which was eliminated by co-application of potassium channel blockers ChTx and Apamin, or endothelial removal. By contrast, adding endothelium cells cultured in vitro together with ACh into the luminal perfusate could mimic non-NO and non-PGI2 relaxation in endothelium-denuded MCA, once CSE was knocked down from endothelium cells, and its effect on vasorelaxation was abolished. Furthermore, the indexes of neuronal injury were measured after cerebral I/R to confirm the neuroprotection of H2S, and we found that the neurological scores, cerebral infarction volume, brain water content, malondialdehyde content, and serum lactate dehydrogenase activity (a marker of cellular membrane integrity) were significantly higher in CSE knockdown rats than in normal control rats. It is not surprising that NaHS could alleviate the cerebral injury. These findings revealed that H2S has a protective effect on cerebral I/R injury via its upregulation of the endothelium-dependent contraction and dilation function of cerebral vessels, which may be related to activating potassium channel.

Endothelium‐derived hydrogen sulfide acts as a hyperpolarizing factor and exerts neuroprotective effects via activation of large‐conductance Ca2+‐activated K+ channels

“…For OGD/R (Chen et al, 2013), hippocampal neurons were subjected to 4 h of hypoxia induced by replacing culture medium with glucose‐free D‐Hank's solution (in mg·L −1 : 8000 NaCl, 400 KCl, 510 Na 2 HPO 4 ·12H 2 O, 60 KH 2 PO 4 and 350 NaHCO 3 , pH 7.2–7.4) under the condition of 94% N 2 , 5% CO 2 and 1% O 2 and 24 h of reoxygenation induced by replacing the glucose‐free D‐Hank's solution with normal culture medium and being incubated under normal condition. In NaHS or the other drug treatment groups, cells were respectively treated with NaHS (1 × 10 −6 M) (Wen et al, 2018), iberiotoxin (100 nM) (Guo et al, 2020), BMS‐191011 (10 μM) (Levin et al, 2016), NNC 55‐0396 (100 μM) (Angstadt et al, 2017) or verapamil (100 μM) (Tang et al, 2016) before and during OGD/R.…”

“…As all we know, the effective therapy of ischaemic stroke depends on a functional vasculature (Palomares & Cipolla, 2011) and especially relies on endothelial vasodilator function (Wen et al, 2019). Hence, vascular protection is regarded as an important therapeutic approach to reduce damage caused by stroke (Wen et al, 2018). Endothelium‐derived hyperpolarizing factor (EDHF), one of the naturally occurring endothelium‐derived relaxing factors (EDRFs), has been found to play a crucial role in mediating blood vessel dilation (Wang, Hu, et al, 2016) and has been suggested as a therapeutic target for ischaemic brain injury (Han et al, 2018).…”

The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System

“…Furthermore, H 2 S has been reported to improve the integrity of the barrier and attenuate cerebral edema, and the reduction of CSE expression close to injury sites coincided with increased Alb extravasation and barrier dysfunction [ 29 , 30 , 31 ]. Denoix et al reported that OTR and CSE were also expressed in the arteries and microvasculature, suggesting that they might play a role in blood–brain barrier integrity [ 25 ].…”

CSE-Derived H2S Inhibits Reactive Astrocytes Proliferation and Promotes Neural Functional Recovery after Cerebral Ischemia/Reperfusion Injury in Mice Via Inhibition of RhoA/ROCK2 Pathway

“…As substrate of H 2 S synthase, l -cysteine, could protect neonatal mice against hypoxia-ischemia injury by inhibiting glial activation . Our previous study revealed that endogenous H 2 S produced by CSE could suppress the RhoA/ROCK signaling pathway and then exert vasoprotective role against acute cerebral I/R damage of mice. , But the long-term effect of CSE-derived H 2 S on the reactive astrocytes proliferation and neural functional recovery following acute cerebral I/R injury is unclear.…”