Vanacore, Domenico (2022) Endogenous cross-talk between hydrogen sulfide and nitric oxide: role of L-serine and L-cysteine in inflammatory vascular diseases. [Tesi di dottorato]

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Gasotransmitters are small bioactive gaseous molecules involved in the regulation of several physiological and pathological processes. This class of gaseous molecules includes hydrogen sulfide (H2S), nitric oxide (NO) and carbon monoxide (CO). H2S is the latest discovered gaseous molecule signaling and it is endogenously produced in mammalian cells mainly from L-cysteine (L-Cys) by the action of cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST). It is well recognized that H2S, as NO, dilates blood vessels (regulating blood pressure), protects tissue from ischemia-reperfusion injury, regulates hormonal metabolism, and is involved in inflammatory process as well in cancer, or acts as neuromodulator. Besides, altered levels or anomalous metabolism of H2S could be implicated in several disorders, including cardiovascular, reproductive, inflammatory, and neurodegenerative diseases. In this scenario, several pieces of evidence have suggested that a crosstalk between H2S and NO and CO exists, since they share many properties, modes of action, or regulatory targets. In particular, NO and H2S are not independent regulators and their physiopathological functions or signaling are often overlapped. Recently, it has been reported an endogenous cross-talk between NO and H2S within the transsulfuration pathway in the vasculature. More in detail, the relaxing effect of L-Cys involves not only H2S but also L-serine (L-Ser), which triggers the sphingosine-1 phosphate (S1P) synthesis mediating NO production. The first part of this thesis is focused on the contribution of H2S in uterine contraction in an animal model of type 1 of diabetes mellitus (T1DM), i.e. non-obese diabetic mice (NOD). Uteri of NOD mice showed a reduction in basal and stimulated contraction coupled to a local increase in H2S production and an over-expression of 3-MST. Thus, the increase of H2S that acting as a non-specific endogenous inhibitor of phosphodiesterase’s activity, caused an elevation of the levels of cGMP and cAMP, responsible for the reduced motility found in diabetic mice. In parallel, we also found that the exposure of isolated uteri to L-Cys, but not to sodium hydrogen sulfide (NaHS), an H2S donor, showed a weak tocolytic effect in the uterus of NOD mice, likely due to the elevated tissue levels of H2S observed. These results may explain the poor uterine contractility and the reproductive disorders occurring in diabetic patients.

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