Historically acknowledged as toxic gases, hydrogen sulfide (H2S) and nitric oxide (NO) are now recognized as the predominant members of a new family of signaling molecules, “gasotransmitters” in mammals. While H2S is biosynthesized by three constitutively expressed enzymes (CBS, CSE, and 3-MST) from L-cysteine and homocysteine, NO is generated endogenously from L-arginine by the action of various isoforms of NOS. Both gases have been transpired as the key and independent regulators of many physiological functions in mammalian cardiovascular, nervous, gastrointestinal, respiratory, and immune systems. The analogy between these two gasotransmitters is evident not only from their paracrine mode of signaling, but also from the identical and/or shared signaling transduction pathways. With the plethora of research in the pathophysiological role of gasotransmitters in various systems, the existence of interplay between these gases is being widely accepted. Chemical interaction between NO and H2S may generate nitroxyl (HNO), which plays a specific effective role within the cardiovascular system. In this review article, we have attempted to provide current understanding of the individual and interactive roles of H2S and NO signaling in mammalian cardiovascular system, focusing particularly on heart contractility, cardioprotection, vascular tone, angiogenesis, and oxidative stress.

No abstract

For more than 300 years, the toxicity of hydrogen sulfide (H2S) has been known to mankind. However, this point of view is changing as an increased interest was observed in H2S biology in the last two decades. The scientific community has succeeded to unravel many important physiological and pathological effects of H2S on mammalian body systems. Thus, H2S is now referred to as a third endogenous gaseous mediator along with nitric oxide and carbon monoxide. Acting as a neuromodulator, H2S facilitates long-term potentiation and regulates intracellular calcium levels, which are important processes in learning and memory. Aberrant endogenous production and metabolism of H2S are implicated in pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). Various H2S donors have shown beneficial therapeutic effects in neurodegenerative disease models by targeting hallmark pathological events (e.g., amyloid-β production in AD and neuroinflammation in PD). The results obtained from many in vivo studies clearly show that H2S not only prevents neuronal and synaptic deterioration but also improves deficits in memory, cognition, and learning. The anti-inflammatory, antioxidant, and anti-apoptotic effects of H2S underlie its neuroprotective properties. In this chapter, we will overview the current understanding of H2S in context of neurodegenerative diseases, with special emphasis on its corrective effects on impaired learning, memory, and cognition.

Alzheimer's disease (AD) is the leading cause of senile dementia in today's society. Its debilitating symptoms are manifested by disturbances in many important brain functions, which are influenced by adenosine. Hence, adenosinergic system is considered as a potential therapeutic target in AD treatment. In the present study, we found that sodium hydrosulfide (NaHS, an H2S donor, 100 µM) attenuated HENECA (a selective A2A receptor agonist, 10–200 nM) induced β-amyloid (1–42) (Aβ42) production in SH-SY5Y cells. NaHS also interfered with HENECA-stimulated production and post-translational modification of amyloid precursor protein (APP) by inhibiting its maturation. Measurement of the C-terminal APP fragments generated from its enzymatic cleavage by β-site amyloid precursor protein cleaving enzyme 1 (BACE1) showed that NaHS did not have any significant effect on β-secretase activity. However, the direct measurements of HENECA-elevated γ-secretase activity and mRNA expressions of presenilins suggested that the suppression of Aβ42 production in NaHS pretreated cells was mediated by inhibiting γ-secretase. NaHS induced reductions were accompanied by similar decreases in intracellular cAMP levels and phosphorylation of cAMP responsive element binding protein (CREB). NaHS significantly reduced the elevated cAMP and Aβ42 production caused by forskolin (an adenylyl cyclase, AC agonist) alone or forskolin in combination with IBMX (a phosphodiesterase inhibitor), but had no effect on those caused by IBMX alone. Moreover, pretreatment with NaHS significantly attenuated HENECA-elevated AC activity and mRNA expressions of various AC isoforms. These data suggest that NaHS may preferentially suppress AC activity when it was stimulated. In conclusion, H2S attenuated HENECA induced Aβ42 production in SH-SY5Y neuroblastoma cells through inhibiting γ-secretase via a cAMP dependent pathway.

No abstract