Abstract
It is well-known that the physiological uterine peristalsis, related to several phases of reproductive functions, plays a pivotal role in fertility and female reproductive health. Here, we have addressed the role of hydrogen sulfide (H2S) signaling in changes of uterine contractions driven by diabetes in non-obese diabetic (NOD) mice, a murine model of type-1 diabetes mellitus. The isolated uterus of NOD mice showed a significant reduction in spontaneous motility coupled to a generalized hypo-contractility to uterotonic agents. The levels of cyclic nucleotides, cAMP and cGMP, notoriously involved in the regulation of uterus homeostasis, were significantly elevated in NOD mouse uteri. This increase was well-correlated with the higher levels of H2S, a non-specific endogenous inhibitor of phosphodiesterases. The exposure of isolated uterus to L-cysteine (L-Cys), but not to sodium hydrogen sulfide, the exogenous source of H2S, showed a weak tocolytic effect in the uterus of NOD mice. Western blot analysis revealed a reorganization of the enzymatic expression with an upregulation of 3-mercaptopyruvate-sulfurtransferase (3-MST) coupled to a reduction in both cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) expression. In conclusion, the increased levels of cyclic nucleotides dysregulate the uterus peristalsis and contractility in diabetic mice through an increase in basal H2S synthesis suggesting a role of 3-MST.
Highlights
Diabetes mellitus (DM), either type-1 diabetes mellitus (T1DM) or type-2 diabetes mellitus (T2DM), is a lifelong condition that affects millions of individuals worldwide [1,2], and it represents a strong risk factor for the development of atherosclerotic coronary and peripheral arterial disease [3,4]
Samples of horn uterus harvested from both control mice (CTR) and NODIII mice were dropped into 5–10 vol Samples of horn uterus harvested from both CTR
The frequency of spontaneous spontaneous motility is significantly reduced in NODIII mice compared to CTR mice (Figure 2B; ***p motility is significantly reduced in NODIII mice compared to CTR mice (Figure 2B; *** p < 0.001)
Summary
Diabetes mellitus (DM), either type-1 diabetes mellitus (T1DM) or type-2 diabetes mellitus (T2DM), is a lifelong condition that affects millions of individuals worldwide [1,2], and it represents a strong risk factor for the development of atherosclerotic coronary and peripheral arterial disease [3,4]. It has been reported that changes in the balance of hydrogen sulfide (H2 S) play an important role in the pathogenesis of β-cell dysfunction that occurs in response to T1DM and T2DM [5,6]. H2 S is synthesized by mammalian tissues, and it serves various important regulatory functions [7,8,9] It is endogenously produced in mammalian cells from the amino acid L-cysteine (L-Cys) through the activation of two pyridoxal-5-phosphate-dependent enzymes, i.e., cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) or 3-mercaptopyruvate-sulfurtransferase (3-MST). Both CSE and CBS are expressed within the pancreas, and H2 S is involved in glucose homeostasis [5]. H2 S production and signaling are Antioxidants 2020, 9, 917; doi:10.3390/antiox9100917 www.mdpi.com/journal/antioxidants
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