Scientific literature about the effect of H2S on pulmonary hypertension is not very rich so far and it deals mostly with animal experiments, so it lacks of human data.
The first evidence of a possible role of H2S in PAH was the finding that H2S could relax the smooth muscle of ileum, portal vein, and thoracic aorta in vitro, and decrease the mean arterial pressure in vivo , and could inhibit the proliferation of cultured aortic vascular smooth muscle cells of rats and humans via inhibition of MAPK activity. Nevertheless, Chunyu et al. conducted the pioneer work: they found out that on an animal model of PH the gene expression and the activity of CSE enzyme in lung tissues as well as H2S levels in plasma were reduced, and that exogenous supply of H2S could alleviate the elevation of pulmonary arterial pressure and improve vascular remodelling . Furthermore, inhibition of CSE by propalglycine could even worsen the hallmarks of PH . Xiahoui et al. further confirmed the same findings of Chunyu et al. by inducing PH in rats with a different method . It is interesting to note that H2S levels were not affected by monocrotaline (MCT) in a rat model of PH , likely because the pathogenesis of MCT-induced PH is different from other animal models.
The improvement of vascular remodelling by H2S was reported to be due to: 1) a reduction of production of collagen I and III, important component of the ECM, by regulating the homeostasis of their synthesis and degradation through the up-regulation of the MMP-13 and the TIMP1 and the reduction of ET-1 and CTGF gene mRNA expression ; 2) apoptosis of pulmonary artery smooth muscle cells via the activation of Fas pathway and the inhibition of Bcl-2 ; and 3) the attenuation of pulmonary smooth muscle cells proliferation . In particular, the latter effect is considered to be a mixture of involvement of both NO and CO: the treatment with exogenous H2S attenuated the activated NO/NOS pathway and increased the production of endogenous CO (reported to inhibit vascular smooth muscle cell (VSMC) proliferation in hypoxic pulmonary hypertension ) and up-regulated the HO-1 protein expression in lung tissue in shunted rats, which might be involved in the mechanisms by which H2S alleviates pulmonary vascular remodelling406. It seems that NO, CO, and H2S might possibly interact under physiological and pathological conditions and they might constitute a regulatory network in the vascular system, in particular in the environment caused by PH, as other works by Yanfei et al. and Zhang et al. may lead us to suggest.
The hypoxic conditions used to induce the animal model of PH are widely known to generate large amounts of ROS, which can induce the progression of pulmonary vascular remodelling. The role of H2S as an antioxidant-preventing agent in the disease was evidenced by the fact that the gasotransmitter could restore the levels of the total antioxidant capacity, and lower the content of oxidized gluthatione in favour of reduced glutathione, as indicator of intracellular redox buffers; the activity of SOD enzymes was not affected by hypoxia neither before nor after administration of H2S .
H2S has been found useful to attenuate proliferation of hPASMCs treated with cobalt chloride (CoCl2), via upergulation of COX-2/PGI2 pathway . CoCl2 is a hypoxia-mimicking agent, which leads to a cellular model of hypoxic PAH; human PASMCs treated with this agent show a marked increase in cell proliferation, accompanied by a decrease in COX-2 expression, PGI2 secretion and H2S levels. Exogenous NaHS suppressed CoCl2-induced proliferation of the cells through the increase in the intracellular content of H2S; importantly, the exposure of the cells to NaHS suppressed the CoCl2-induced down-regulation in COX-2 expression and PGI2 secretion from the HPASMCs.
Finally yet importantly, H2S has been proved to relax human pulmonary arteries pre-contracted with potassium chloride in a concentration-dependent manner and this effect is independent of the integrity of the endothelium; however, the mechanisms by which H2S exerts these effects have not been investigated. In another paper, Sun et al. compared the vasorelaxing effect of exogenous H2S in rat aorta and pulmonary artery: NaHS was able to induce a more pronounced vasorelaxation in aorta, compared to pulmonary artery . They postulated that H2S could open more widely KATP channels in aorta rather than pulmonary artery because of a higher presence of subunit SUR2B of KATP channels in the former; furthermore, in pulmonary artery only glibenclamide (a blocker of cellular KATP channels) affected the vasorelaxation, compared to aorta, in which both glibenclamide and 5-hydroxydecanoate (a blocker of mithocondrial KATP channels) could reduce vasorelaxation, thus further supporting their thesis.
Therefore, the molecular and cellular mechanisms by which H2S/??-cysteine pathway affects PH are still not fully understood and needs further exploration.
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