Gestational Exposure to Cigarette Smoke Suppresses the Gasotransmitter H2S Biogenesis and the Effects Are Transmitted Transgenerationally.

Rationale: Gestational cigarette smoke (CS) impairs lung angiogenesis and alveolarization, promoting transgenerational development of asthma and bronchopulmonary dysplasia (BPD). Hydrogen sulfide (H2S), a proangiogenic, pro-alveolarization, and anti-asthmatic gasotransmitter is synthesized by cystathionine-γ-lyase (CSE), cystathionine-ß-synthase (CBS), and 3-mercaptopyruvate sulfur transferase (3MST). Objective: Determine if gestational CS exposure affected the expression of H2S synthesizing enzymes in the mouse lung and human placenta. Methods: Mice were exposed throughout gestational period to secondhand CS (SS) at approximating the dose of CS received by a pregnant woman sitting in a smoking bar for 3 h/days during pregnancy. Lungs from 7-days old control and SS-exposed pups and human placenta from mothers who were either non-smokers or smokers during pregnancy were analyzed for expression of the enzymes. Measurements: Mouse lungs and human placentas were examined for the expression of CSE, CBS, and 3MST by immunohistochemical staining, qRT-PCR and/or Western blot (WB) analyses. Results: Compared to controls, mouse lung exposed gestationally to SS had significantly lower levels of CSE, CBS, and 3MST. Moreover, the SS-induced suppression of CSE and CBS in F1 lungs was transmitted to the F2 generation without significant change in the magnitude of the suppression. These changes were associated with impaired epithelial-mesenchymal transition (EMT)-a process required for normal lung angiogenesis and alveolarization. Additionally, the placentas from mothers who smoked during pregnancy, expressed significantly lower levels of CSE, CBS, and 3MST, and the effects were partially moderated by quitting smoking during the first trimester. Conclusions: Lung H2S synthesizing enzymes are downregulated by gestational CS and the effects are transmitted to F2 progeny. Smoking during pregnancy decreases H2S synthesizing enzymes is human placentas, which may correlate with the increased risk of asthma/BPD in children.

Inhibition of gasotransmitters production and calcium influx affect cardiodynamic variables and cardiac oxidative stress in propofol-anesthetized male Wistar rats 1.

It has been assumed that the cardioprotective effects of propofol are due to its non-anesthetic pleiotropic cardiac and vasodilator effects, in which gasotransmitters (NO, H2S, and CO) as well as calcium influx could be involved. The study on isolated rat heart was performed using 4 experimental groups (n = 7 in each): (1) bolus injection of propofol (100 mg/kg body mass, i.p.); (2) L-NAME (NO synthase inhibitor, 60 mg/kg body mass, i.p.) + propofol; (3) DL-PAG (H2S synthase inhibitor, 50 mg/kg body mass, i.p.) + propofol; (4) ZnPPIX (CO synthase inhibitor, 50 µmol/kg body mass, i.p.) + propofol. Before and after the verapamil (3 µmol/L) administration, cardiodynamic parameters were recorded (dp/dtmax, dp/dtmin, systolic left ventricular pressure, diastolic left ventricular pressure, heart rate, coronary flow), as well as coronary and cardiac oxidative stress parameters. The results showed significant increases of diastolic left ventricular pressure following NO and CO inhibition, but also increases of coronary flow following H2S and CO inhibition. Following verapamil administration, significant decreases of dp/dtmax were noted after NO and CO inhibition, then increase of diastolic left ventricular pressure following CO inhibition, and increase of coronary flow following NO, H2S, or CO inhibition. Oxidative stress markers were increased but catalase activity was significantly decreased in cardiac tissue. Gasotransmitters and calcium influx are involved in pleiotropic cardiovascular effects of propofol in male Wistar rats.

Gasotransmitters in cancer: from pathophysiology to experimental therapy.

The three endogenous gaseous transmitters - nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) - regulate a number of key biological functions. Emerging data have revealed several new mechanisms for each of these three gasotransmitters in tumour biology. It is now appreciated that they show bimodal pharmacological character in cancer, in that not only the inhibition of their biosynthesis but also elevation of their concentration beyond a certain threshold can exert anticancer effects. This Review discusses the role of each gasotransmitter in cancer and the effects of pharmacological agents - some of which are in early-stage clinical studies - that modulate the levels of each gasotransmitter. A clearer understanding of the pharmacological character of these three gases and the mechanisms underlying their biological effects is expected to guide further clinical translation.

Reciprocal interaction among gasotransmitters in isolated pancreatic ß-cells.

We aimed to elucidate the interplay among the three well-known gas molecules, nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), and their effects on intracellular Ca(2+) concentration ([Ca(2+)]i) and insulin secretion in rat pancreatic ß-cells. Immunofluorescence studies demonstrated the expression of constitutive enzymes that are responsible for the production of NO, CO and H2S. CO and H2S increased NO production as indicated by the increase in diaminofluorescein-2 triazole fluorescence. NO and CO induced an elevation in the sulfane sulfur pool and concomitantly H2S production. The NO- and CO-induced H2S production was partially inhibited by hypotaurine, an H2S scavenger. NO and H2S produced CO production as revealed by a myoglobin assay. A calmodulin antagonist in the absence of extracellular Ca(2+) significantly attenuated NO and H2S production. NO and CO induced a [Ca(2+)]i increase mainly via Ca(2+) release from internal stores; however, H2S induced a [Ca(2+)]i increase via the influx of extracellular Ca(2+). NO dose-dependently stimulated basal insulin release but CO dose-dependently inhibited it. H2S showed an insignificant effect on basal insulin secretion from freshly isolated pancreatic islets. Herein, we address for the first time the reciprocal and synergistic relation among gasotransmitters with diverse effects on basal insulin secretion that regulate ß-cells functions and homeostasis.

A critical review of pharmacological significance of Hydrogen Sulfide in hypertension.

In the family of gas transmitters, hydrogen sulfide (H2S) is yet not adequately researched. Known for its rotten egg smell and adverse effects on the brain, lungs, and kidneys for more than 300 years, the vasorelaxant effects of H2S on blood vessel was first observed in 1997. Since then, research continued to explore the possible therapeutic effects of H2S in hypertension, inflammation, pancreatitis, different types of shock, diabetes, and heart failure. However, a considerable amount of efforts are yet needed to elucidate the mechanisms involved in the therapeutic effects of H2S, such as nitric oxide-dependent or independent vasodilation in hypertension and regression of left ventricular hypertrophy. More than a decade of good repute among researchers, H2S research has certain results that need to be clarified or reevaluated. H2S produces its response by multiple modes of action, such as opening the ATP-sensitive potassium channel, angiotensin-converting enzyme inhibition, and calcium channel blockade. H2S is endogenously produced from two sulfur-containing amino acids L-cysteine and L-methionine by the two enzymes cystathionine γ lyase and cystathionine ß synthase. Recently, the third enzyme, 3-mercaptopyruvate sulfur transferase, along with cysteine aminotransferase, which is similar to aspartate aminotransferase, has been found to produce H2S in the brain. The H2S has interested researchers, and a great deal of information is being generated every year. This review aims to provide an update on the developments in the research of H2S in hypertension amid the ambiguity in defining the exact role of H2S in hypertension because of insufficient number of research results on this area. This critical review on the role of H2S in hypertension will clarify the gray areas and highlight its future prospects.